Updated on 2024/04/18

写真a

 
HATTORI Takako
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Assistant Professor
Position
Assistant Professor
External link

Degree

  • 博士(歯学) ( 岡山大学 )

Research Interests

  • 分子生物学

  • 口腔生化学

  • 関節リウマチ

  • 発生生物学

  • cell biology

  • transcriptional control

  • bone

  • circadian rhythm

  • Sox9

  • CCN family proteins

  • osteoarthritis

  • articular cartilage

  • anti-aging

  • endochondral bone formation

  • cartilage

  • 時計遺伝子

  • 老化

  • トランスクリプトーム解析

Research Areas

  • Life Science / Oral biological science  / Oral biochemistry

  • Life Science / Molecular biology

  • Life Science / Oral pathobiological science

  • Life Science / Cell biology

Education

  • Okayama University   理学部   生物

    - 1990

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    Country: Japan

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  • 岡山大学大学院   歯学研究科  

    2000.9

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    Notes: 博士(歯学)

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Research History

  • Department of Orthopaedics, University of Maryland School of Medicine(米国)

    2023.2 - 2023.3

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    Country:United States

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  • - Assistant Professor,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama University

    2004

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  • - 岡山大学医歯薬学総合研究科 助教

    2004

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  • Researcher,Department of Molecular Genetics, MD Anderson Cancer Center, The University of Texas

    2001 - 2004

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Professional Memberships

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Committee Memberships

  •   岡山大学臨床研究審査専門委員会委員  

    2021.4   

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    Committee type:Other

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  • 日本CCNファミリー研究会   事務局  

    2004.4   

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Papers

  • Do not overwork: cellular communication network factor 3 for life in cartilage. Reviewed International journal

    Satoshi Kubota, Harumi Kawaki, Bernard Perbal, Masaharu Takigawa, Kazumi Kawata, Takako Hattori, Takashi Nishida

    Journal of cell communication and signaling   17 ( 2 )   353 - 359   2023.6

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    Cellular communication network factor (CCN) 3, which is one of the founding members of the CCN family, displays diverse functions. However, this protein generally represses the proliferation of a variety of cells. Along with skeletal development, CCN3 is produced in cartilaginous anlagen, growth plate cartilage and epiphysial cartilage. Interestingly, CCN3 is drastically induced in the growth plates of mice lacking CCN2, which promotes endochondral ossification. Notably, chondrocytes in these mutant mice with elevated CCN3 production also suffer from impaired glycolysis and energy metabolism, suggesting a critical role of CCN3 in cartilage metabolism. Recently, CCN3 was found to be strongly induced by impaired glycolysis, and in our study, we located an enhancer that mediated CCN3 regulation via starvation. Subsequent investigations specified regulatory factor binding to the X-box 1 (RFX1) as a transcription factor mediating this CCN3 regulation. Impaired glycolysis is a serious problem, resulting in an energy shortage in cartilage without vasculature. CCN3 produced under such starved conditions restricts energy consumption by repressing cell proliferation, leading chondrocytes to quiescence and survival. This CCN3 regulatory system is indicated to play an important role in articular cartilage maintenance, as well as in skeletal development. Furthermore, CCN3 continues to regulate cartilage metabolism even during the aging process, probably utilizing this regulatory system. Altogether, CCN3 seems to prevent "overwork" by chondrocytes to ensure their sustainable life in cartilage by sensing energy metabolism. Similar roles are suspected to exist in relation to systemic metabolism, since CCN3 is found in the bloodstream.

    DOI: 10.1007/s12079-023-00723-4

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  • Elevated Expression of CCN3 in Articular Cartilage Induces Osteoarthritis in Hip Joints Irrespective of Age and Weight Bearing. Reviewed International journal

    Kazuki Hirose, Miho Kuwahara, Eiji Nakata, Tomonori Tetsunaga, Kazuki Yamada, Kenta Saiga, Masaharu Takigawa, Toshifumi Ozaki, Satoshi Kubota, Takako Hattori

    International journal of molecular sciences   23 ( 23 )   2022.12

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    Osteoarthritis (OA) occurs not only in the knee but also in peripheral joints throughout the whole body. Previously, we have shown that the expression of cellular communication network factor 3 (CCN3), a matricellular protein, increases with age in knee articular cartilage, and the misexpression of CCN3 in cartilage induces senescence-associated secretory phenotype (SASP) factors, indicating that CCN3 promotes cartilage senescence. Here, we investigated the correlation between CCN3 expression and OA degenerative changes, principally in human femoral head cartilage. Human femoral heads obtained from patients who received total hip arthroplasty were categorized into OA and femoral neck fracture (normal) groups without significant age differences. Gene expression analysis of RNA obtained from femoral head cartilage revealed that CCN3 and MMP-13 expression in the non-weight-bearing part was significantly higher in the OA group than in the normal group, whereas the weight-bearing OA parts and normal cartilage showed no significant differences in the expression of these genes. The expression of COL10A1, however, was significantly higher in weight-bearing OA parts compared with normal weight-bearing parts, and was also higher in weight-bearing parts compared with non-weight-bearing parts in the OA group. In contrast, OA primary chondrocytes from weight-bearing parts showed higher expression of CCN3, p16, ADAMTS4, and IL-1β than chondrocytes from the corresponding normal group, and higher ADAMTS4 and IL-1β in the non-weight-bearing part compared with the corresponding normal group. Acan expression was significantly lower in the non-weight-bearing group in OA primary chondrocytes than in the corresponding normal chondrocytes. The expression level of CCN3 did not show significant differences between the weight-bearing part and non-weight-bearing part in both OA and normal primary chondrocytes. Immunohistochemical analysis showed accumulated CCN3 and aggrecan neoepitope staining in both the weight-bearing part and non-weight-bearing part in the OA group compared with the normal group. The CCN3 expression level in cartilage had a positive correlation with the Mankin score. X-ray analysis of cartilage-specific CCN3 overexpression mice (Tg) revealed deformation of the femoral and humeral head in the early stage, and immunohistochemical analysis showed accumulated aggrecan neoepitope staining as well as CCN3 staining and the roughening of the joint surface in Tg femoral and humeral heads. Primary chondrocytes from the Tg femoral head showed enhanced expression of Ccn3, Adamts5, p16, Il-6, and Tnfα, and decreased expression of Col2a1 and -an. These findings indicate a correlation between OA degenerative changes and the expression of CCN3, irrespective of age and mechanical loading. Furthermore, the Mankin score indicates that the expression level of Ccn3 correlates with the progression of OA.

    DOI: 10.3390/ijms232315311

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  • Molecular and Genetic Interactions between CCN2 and CCN3 behind Their Yin-Yang Collaboration. Reviewed International journal

    Satoshi Kubota, Kazumi Kawata, Takako Hattori, Takashi Nishida

    International journal of molecular sciences   23 ( 11 )   2022.5

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    Cellular communication network factor (CCN) 2 and 3 are the members of the CCN family that conduct the harmonized development of a variety of tissues and organs under interaction with multiple biomolecules in the microenvironment. Despite their striking structural similarities, these two members show contrastive molecular functions as well as temporospatial emergence in living tissues. Typically, CCN2 promotes cell growth, whereas CCN3 restrains it. Where CCN2 is produced, CCN3 disappears. Nevertheless, these two proteins collaborate together to execute their mission in a yin-yang fashion. The apparent functional counteractions of CCN2 and CCN3 can be ascribed to their direct molecular interaction and interference over the cofactors that are shared by the two. Recent studies have revealed the mutual negative regulation systems between CCN2 and CCN3. Moreover, the simultaneous and bidirectional regulatory system of CCN2 and CCN3 is also being clarified. It is of particular note that these regulations were found to be closely associated with glycolysis, a fundamental procedure of energy metabolism. Here, the molecular interplay and metabolic gene regulation that enable the yin-yang collaboration of CCN2 and CCN3 typically found in cartilage development/regeneration and fibrosis are described.

    DOI: 10.3390/ijms23115887

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  • Maternal Gut Microbiome Decelerates Fetal Endochondral Bone Formation by Inducing Inflammatory Reaction. Reviewed International journal

    Yoko Uchida-Fukuhara, Takako Hattori, Shanqi Fu, Sei Kondo, Miho Kuwahara, Daiki Fukuhara, Md Monirul Islam, Kota Kataoka, Daisuke Ekuni, Satoshi Kubota, Manabu Morita, Mika Iikegame, Hirohiko Okamura

    Microorganisms   10 ( 5 )   2022.5

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    To investigate the effect of the maternal gut microbiome on fetal endochondral bone formation, fetuses at embryonic day 18 were obtained from germ-free (GF) and specific-pathogen-free (SPF) pregnant mothers. Skeletal preparation of the fetuses' whole bodies did not show significant morphological alterations; however, micro-CT analysis of the tibiae showed a lower bone volume fraction in the SPF tibia. Primary cultured chondrocytes from fetal SPF rib cages showed a lower cell proliferation and lower accumulation of the extracellular matrix. RNA-sequencing analysis showed the induction of inflammation-associated genes such as the interleukin (IL) 17 receptor, IL 6, and immune-response genes in SPF chondrocytes. These data indicate that the maternal gut microbiome in SPF mice affects fetal embryonic endochondral ossification, possibly by changing the expression of genes related to inflammation and the immune response in fetal cartilage. The gut microbiome may modify endochondral ossification in the fetal chondrocytes passing through the placenta.

    DOI: 10.3390/microorganisms10051000

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  • Cysteinyl leukotriene receptor 1 is dispensable for osteoclast differentiation and bone resorption. Reviewed International journal

    Hirofumi Fujita, Aoi Ando, Yohei Mizusawa, Mitsuaki Ono, Takako Hattori, Munenori Habuta, Toshitaka Oohashi, Satoshi Kubota, Hideyo Ohuchi

    PloS one   17 ( 11 )   e0277307   2022

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    Cysteinyl leukotriene receptor 1 (CysLTR1) is a G protein-coupled receptor for the inflammatory lipid mediators cysteinyl leukotrienes, which are involved in smooth muscle constriction, vascular permeability, and macrophage chemokine release. The Cysltr1 gene encoding CysLTR1 is expressed in the macrophage lineage, including osteoclasts, and the CysLTR1 antagonist Montelukast has been shown to suppress the formation of osteoclasts. However, it currently remains unclear whether CysLTR1 is involved in osteoclast differentiation and bone loss. Therefore, to clarify the role of CysLTR1 in osteoclastogenesis and pathological bone loss, we herein generated CysLTR1 loss-of-function mutant mice by disrupting the cysltr1 gene using the CRISPR-Cas9 system. These mutant mice had a frameshift mutation resulting in a premature stop codon (Cysltr1 KO) or an in-frame mutation causing the deletion of the first extracellular loop (Cysltr1Δ105). Bone marrow macrophages (BMM) from these mutant mice lost the intracellular flux of calcium in response to leukotriene D4, indicating that these mutants completely lost the activity of CysLTR1 without triggering genetic compensation. However, disruption of the Cysltr1 gene did not suppress the formation of osteoclasts from BMM in vitro. We also demonstrated that the CysLTR1 antagonist Montelukast suppressed the formation of osteoclasts without functional CysLTR1. On the other hand, disruption of the Cysltr1 gene partially suppressed the formation of osteoclasts stimulated by leukotriene D4 and did not inhibit that by glutathione, functioning as a substrate in the synthesis of cysteinyl leukotrienes. Disruption of the Cysltr1 gene did not affect ovariectomy-induced osteoporosis or lipopolysaccharide-induced bone resorption. Collectively, these results suggest that the CysLT-CysLTR1 axis is dispensable for osteoclast differentiation in vitro and pathological bone loss, while the leukotriene D4-CysTR1 axis is sufficient to stimulate osteoclast formation. We concluded that the effects of glutathione and Montelukast on osteoclast formation were independent of CysLTR1.

    DOI: 10.1371/journal.pone.0277307

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  • Cellular communication network factor 3 in cartilage development and maintenance. Reviewed International journal

    Satoshi Kubota, Harumi Kawaki, Bernard Perbal, Kazumi Kawata, Takako Hattori, Takashi Nishida

    Journal of cell communication and signaling   15 ( 4 )   533 - 543   2021.12

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    Cellular communication network factor (CCN) 3 is one of the classical members of the CCN family, which are characterized by common molecular structures and multiple functionalities. Although this protein was discovered as a gene product overexpressed in a truncated form in nephroblastoma, recent studies have revealed its physiological roles in the development and homeostasis of mammalian species, in addition to its pathological association with a number of diseases. Cartilage is a tissue that creates most of the bony parts and cartilaginous tissues that constitute the human skeleton, in which CCN3 is also differentially produced to exert its molecular missions therein. In this review article, after the summary of the molecular structure and function of CCN3, recent findings on the regulation of ccn3 expression and the roles of CCN3 in endochondral ossification, cartilage development, maintenance and disorders are introduced with an emphasis on the metabolic regulation and function of this matricellular multifunctional molecule.

    DOI: 10.1007/s12079-021-00629-z

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    Other Link: https://link.springer.com/article/10.1007/s12079-021-00629-z/fulltext.html

  • UCP1 expression in the mouse adrenal gland is not upregulated by thermogenic conditions. Reviewed International journal

    Hirofumi Fujita, Munenori Habuta, Takako Hattori, Satoshi Kubota, Hiromi Kumon, Hideyo Ohuchi

    Biochemical and biophysical research communications   566   184 - 189   2021.8

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    The uncoupling protein 1 (UCP1) gene is known to be highly expressed in brown adipose tissue (BAT) that functions in thermogenesis. It has been shown that UCP1 mRNA is localized to the mouse adrenal gland, but its significance remains elusive. To explore how UCP1 expression in the adrenal gland is regulated, we generated a reporter knock-in mouse in which the GFP gene was inserted into the UCP1 locus using CRISPR-Cas9 system. Firstly, we confirmed by Western blot analysis UCP1-driven GFP protein expression in interscapular BAT of the knock-in mice kept at 4 °C. Immunohistochemistry showed that GFP protein was detected in the adrenal gland of the knock-in mice. More intense GFP expression was observed in the adrenal medulla than in the cortex of the reporter mice irrespectively of cold exposure. Immunohistochemistry using anti-UCP1 antibody, as well as Western blot analysis verified UCP1 protein expression in the wild-type adrenal medulla. These results suggest that the mouse adrenal gland is a novel organ expressing UCP1 protein and its expression is not upregulated by cold exposure.

    DOI: 10.1016/j.bbrc.2021.06.013

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  • Bipartite regulation of cellular communication network factor 2 and fibroblast growth factor 1 genes by fibroblast growth factor 1 through histone deacetylase 1 and fork head box protein A1. Reviewed International journal

    Abdellatif Elseoudi, Takashi Nishida, Tomomi Mizukawa, Takako Hattori, Kazumi Kawata, Eman A Taha, Masaharu Takigawa, Satoshi Kubota

    Journal of cell communication and signaling   15 ( 1 )   81 - 91   2021.3

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    Fibroblast growth factor 1 (FGF-1) is the first FGF family member, and it induces proliferation of fibroblasts and other types of the cells. However, recent studies are uncovering unexpected functions of this molecule. Our previous study redefined this growth factor as a catabolic molecule produced in cartilage upon metabolic insult. Indeed, FGF-1 was found to repress the gene expression of cellular communication network factor 2 (CCN2), which protects and regenerates cartilage, amplifying its own production through positive feedback regulation. In the present study, we investigated the molecular mechanism of this bipartite CCN2 repression and FGF1 activation by FGF-1 in chondrocytes. Repression of CCN2 and induction of FGF1 in human chondrocytic cells were both partly abolished by valproic acid, an inhibitor of histone deacetylase 1 (HDAC1), indicating the involvement of chromatin remodeling by histone acetylation in this system. In contrast, RNA degradation analysis suggested no contribution of post-transcriptional regulation of the mRNA stability to the effects conferred by FGF-1. Suspecting a regulation by a specific transcription factor, we next sought a candidate in silico from a large dataset. As a result, we found fork head box protein A1 (FOXA1) as the transcription factor that bound to both CCN2 and FGF1 loci. Functional analysis demonstrated that FOXA1 silencing significantly attenuated the CCN2 repression and FGF1 induction caused by FGF1. These findings collectively indicate that the bipartite regulation by FGF-1 is enabled by the combination of chromatin remodeling by HDACs and transcriptional modulation by FOXA1 with unknown transcriptional coactivators of opposite functionalities.

    DOI: 10.1007/s12079-020-00600-4

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  • CCN3 (NOV) Drives Degradative Changes in Aging Articular Cartilage Reviewed International journal

    Miho Kuwahara, Koichi Kadoya, Sei Kondo, Shanqi Fu, Yoshiko Miyake, Ayako Ogo, Mitsuaki Ono, Takayuki Furumatsu, Eiji Nakata, Takako Sasaki, Shogo Minagi, Masaharu Takigawa, Satoshi Kubota, Takako Hattori

    International Journal of Molecular Sciences   21 ( 20 )   7556 - 7556   2020.10

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    Aging is a major risk factor of osteoarthritis, which is characterized by the degeneration of articular cartilage. CCN3, a member of the CCN family, is expressed in cartilage and has various physiological functions during chondrocyte development, differentiation, and regeneration. Here, we examine the role of CCN3 in cartilage maintenance. During aging, the expression of Ccn3 mRNA in mouse primary chondrocytes from knee cartilage increased and showed a positive correlation with p21 and p53 mRNA. Increased accumulation of CCN3 protein was confirmed. To analyze the effects of CCN3 in vitro, either primary cultured human articular chondrocytes or rat chondrosarcoma cell line (RCS) were used. Artificial senescence induced by H2O2 caused a dose-dependent increase in Ccn3 gene and CCN3 protein expression, along with enhanced expression of p21 and p53 mRNA and proteins, as well as SA-β gal activity. Overexpression of CCN3 also enhanced p21 promoter activity via p53. Accordingly, the addition of recombinant CCN3 protein to the culture increased the expression of p21 and p53 mRNAs. We have produced cartilage-specific CCN3-overexpressing transgenic mice, and found degradative changes in knee joints within two months. Inflammatory gene expression was found even in the rib chondrocytes of three-month-old transgenic mice. Similar results were observed in human knee articular chondrocytes from patients at both mRNA and protein levels. These results indicate that CCN3 is a new senescence marker of chondrocytes, and the overexpression of CCN3 in cartilage may in part promote chondrocyte senescence, leading to the degeneration of articular cartilage through the induction of p53 and p21.

    DOI: 10.3390/ijms21207556

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  • CTGF/CCN2 facilitates LRP4-mediated formation of the embryonic neuromuscular junction. Reviewed International journal

    Bisei Ohkawara, Akinori Kobayakawa, Shunsuke Kanbara, Takako Hattori, Satoshi Kubota, Mikako Ito, Akio Masuda, Masaharu Takigawa, Karen M Lyons, Naoki Ishiguro, Kinji Ohno

    EMBO reports   21 ( 8 )   e48462   2020.6

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    At the neuromuscular junction (NMJ), lipoprotein-related receptor 4 (LRP4) mediates agrin-induced MuSK phosphorylation that leads to clustering of acetylcholine receptors (AChRs) in the postsynaptic region of the skeletal muscle. Additionally, the ectodomain of LRP4 is necessary for differentiation of the presynaptic nerve terminal. However, the molecules regulating LRP4 have not been fully elucidated yet. Here, we show that the CT domain of connective tissue growth factor (CTGF/CCN2) directly binds to the third beta-propeller domain of LRP4. CTGF/CCN2 enhances the binding of LRP4 to MuSK and facilitates the localization of LRP4 on the plasma membrane. CTGF/CCN2 enhances agrin-induced MuSK phosphorylation and AChR clustering in cultured myotubes. Ctgf-deficient mouse embryos (Ctgf-/- ) have small AChR clusters and abnormal dispersion of synaptic vesicles along the motor axon. Ultrastructurally, the presynaptic nerve terminals have reduced numbers of active zones and mitochondria. Functionally, Ctgf-/- embryos exhibit impaired NMJ signal transmission. These results indicate that CTGF/CCN2 interacts with LRP4 to facilitate clustering of AChRs at the motor endplate and the maturation of the nerve terminal.

    DOI: 10.15252/embr.201948462

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  • Roles of Interaction between CCN2 and Rab14 in Aggrecan Production by Chondrocytes. Reviewed International journal

    Mitsuhiro Hoshijima, Takako Hattori, Eriko Aoyama, Takashi Nishida, Satoshi Kubota, Hiroshi Kamioka, Masaharu Takigawa

    International journal of molecular sciences   21 ( 8 )   E2769 - E2769   2020.4

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:MDPI  

    To identify proteins that cooperate with cellular communication network factor 2 (CCN2), we carried out GAL4-based yeast two-hybrid screening using a cDNA library derived from the chondrocytic cell line HCS-2/8. Rab14 GTPase (Rab14) polypeptide was selected as a CCN2-interactive protein. The interaction between CCN2 and Rab14 in HCS-2/8 cells was confirmed using the in situ proximity ligation assay. We also found that CCN2 interacted with Rab14 through its IGFBP-like domain among the four domains in CCN2 protein. To detect the colocalization between CCN2 and Rab14 in the cells in detail, CCN2, wild-type Rab14 (Rab14WT), a constitutive active form (Rab14CA), and a dominant negative form (Rab14DN) of Rab14 were overexpressed in monkey kidney-tissue derived COS7 cells. Ectopically overexpressed Rab14 showed a diffuse cytosolic distribution in COS7 cells; however, when Rab14WT was overexpressed with CCN2, the Rab14WT distribution changed to dots that were evenly distributed within the cytosol, and both Rab14 and CCN2 showed clear colocalization. When Rab14CA was overexpressed with CCN2, Rab14CA and CCN2 also showed good localization as dots, but their distribution was more widespread within cytosol. The coexpression of Rab14DN and CCN2 also showed a dotted codistribution but was more concentrated in the perinuclear area. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis revealed that the reduction in RAB14 or CCN2 mRNA by their respective siRNA significantly enhanced the expression of ER stress markers, BIP and CHOP mRNA in HCS-2/8 chondrocytic cells, suggesting that ER and Golgi stress were induced by the inhibition of membrane vesicle transfer via the suppression of CCN2 or Rab14. Moreover, to study the effect of the interaction between CCN2 and its interactive protein Rab14 on proteoglycan synthesis, we overexpressed Rab14WT or Rab14CA or Rab14DN in HCS-2/8 cells and found that the overexpression of Rab14DN decreased the extracellular proteoglycan accumulation more than the overexpression of Rab14WT/CA did in the chondrocytic cells. These results suggest that intracellular CCN2 is associated with Rab14 on proteoglycan-containing vesicles during their transport from the Golgi apparatus to endosomes in chondrocytes and that this association may play a role in proteoglycan secretion by chondrocytes.

    DOI: 10.3390/ijms21082769

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  • Retrotransposons Manipulating Mammalian Skeletal Development in Chondrocytes. Invited Reviewed International journal

    Satoshi Kubota, Takanori Ishikawa, Kazumi Kawata, Takako Hattori, Takashi Nishida

    International journal of molecular sciences   21 ( 5 )   1564 - 1564   2020.2

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    Retrotransposons are genetic elements that copy and paste themselves in the host genome through transcription, reverse-transcription, and integration processes. Along with their proliferation in the genome, retrotransposons inevitably modify host genes around the integration sites, and occasionally create novel genes. Even now, a number of retrotransposons are still actively editing our genomes. As such, their profound role in the evolution of mammalian genomes is obvious; thus, their contribution to mammalian skeletal evolution and development is also unquestionable. In mammals, most of the skeletal parts are formed and grown through a process entitled endochondral ossification, in which chondrocytes play central roles. In this review, current knowledge on the evolutional, physiological, and pathological roles of retrotransposons in mammalian chondrocyte differentiation and cartilage development is summarized. The possible biological impact of these mobile genetic elements in the future is also discussed.

    DOI: 10.3390/ijms21051564

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  • Circadian production of melatonin in cartilage modifies rhythmic gene expression. Reviewed International journal

    Fu S, Kuwahara M, Uchida Y, Koudo S, Hayashi D, Shimomura Y, Takagaki A, Nishida T, Maruyama Y, Ikegame M, Hattori A, Kubota S, Hattori T

    The Journal of endocrinology   241 ( 2 )   161 - 173   2019.3

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Bioscientifica  

    Endochondral ossification, including bone growth and other metabolic events, is regulated by circadian rhythms. Herein, we provide evidence that melatonin has a direct effect on the circadian rhythm of chondrocytes. We detected mRNA expression of the genes which encode the melatonin-synthesizing enzymes AANAT (arylalkylamine N-acetyltransferase) and HIOMT (hydroxyindole O-methyltransferase), as well as the melatonin receptors MT1 and MT2 in mouse primary chondrocytes and cartilage. Production of melatonin was confirmed by mass spectrometric analysis of primary rat and chick chondrocytes. Addition of melatonin to primary BALB/c mouse chondrocytes caused enhanced cell growth and increased expression of <italic>Col2a1</italic>, <italic>Aggrecan</italic> and <italic>Sox9</italic>, but inhibited <italic>Col10a1</italic> expression. Addition of luzindole, an MT1 and MT2 antagonist, abolished these effects. These data indicate that chondrocytes produce melatonin, which regulates cartilage growth and maturation via the MT1 and MT2 receptors. Kinetic analysis showed that melatonin caused rapid upregulation of <italic>Aanat</italic>, <italic>Mt1</italic>, <italic>Mt2</italic> and <italic>Pthrp</italic> expression, followed by <italic>Sox9</italic> and <italic>Ihh</italic>. Furthermore, expression of the clock gene <italic>Bmal1</italic> was induced, while that of <italic>Per1</italic> was downregulated. Chronobiological analysis of synchronized C3H mouse chondrocytes revealed that melatonin induced the cyclic expression of <italic>Aanat</italic> and modified the cyclic rhythm of <italic>Bmal1</italic>, <italic>Mt1</italic> and <italic>Mt2</italic>. In contrast, <italic>Mt1</italic> and <italic>Mt2</italic> showed different rhythms from <italic>Bmal1</italic> and <italic>Aanat</italic>, indicating the existence of different regulatory genes. Our results indicate that exogenous and endogenous melatonin work in synergy in chondrocytes to adjust rhythmic expression to the central suprachiasmatic nucleus clock.

    DOI: 10.1530/JOE-19-0022

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  • New function of Tip60 in controlling triacylglycerol synthesis Invited Reviewed

    Takako Hattori

    Biotarget   2   13 - 13   2018.9

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    Authorship:Lead author, Last author, Corresponding author   Publishing type:Research paper (scientific journal)   Publisher:AME Publishing Company  

    DOI: 10.21037/biotarget.2018.08.03

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  • Commensal Microbiota Enhance Both Osteoclast and Osteoblast Activities. Reviewed International journal

    Uchida Y, Irie K, Fukuhara D, Kataoka K, Hattori T, Ono M, Ekuni D, Kubota S, Morita M

    Molecules (Basel, Switzerland)   23 ( 7 )   doi: 10, 3390/molecules2307/1517.   2018.6

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    Recent studies suggest that the commensal microbiota affects not only host energy metabolism and development of immunity but also bone remodeling by positive regulation of osteoclast activity. However, the mechanism of regulation of bone cells by the commensal microbiota has not been elucidated. In this study, 8-week-old specific pathogen-free (SPF) and germ-free (GF) mice were compared in terms of alveolar bones and primary osteoblasts isolated from calvarias. Micro-CT analysis showed that SPF mice had larger body size associated with lower bone mineral density and bone volume fraction in alveolar bones compared with GF mice. Greater numbers of osteoclasts in alveolar bone and higher serum levels of tartrate-resistant acid phosphatase 5b were observed in SPF mice. Tissue extracts from SPF alveolar bone showed higher levels of cathepsin K, indicating higher osteoclast activity. SPF alveolar extracts also showed elevated levels of γ-carboxylated glutamic acid⁻osteocalcin as a marker of mature osteoblasts compared with GF mice. Polymerase chain reaction (PCR) array analysis of RNA directly isolated from alveolar bone showed that in SPF mice, expression of mRNA of osteocalcin, which also acts as an inhibitor of bone mineralization, was strongly enhanced compared with GF mice. Cultured calvarial osteoblasts from SPF mice showed reduced mineralization but significantly enhanced expression of mRNAs of osteocalcin, alkaline phosphatase, insulin-like growth factor-I/II, and decreased ratio of osteoprotegerin/receptor activator of nuclear factor-kappa B ligand compared with GF mice. Furthermore, PCR array analyses of transcription factors in cultured calvarial osteoblasts showed strongly upregulated expression of Forkhead box g1. In contrast, Gata-binding protein 3 was strongly downregulated in SPF osteoblasts. These results suggest that the commensal microbiota prevents excessive mineralization possibly by stimulating osteocalcin expression in osteoblasts, and enhances both osteoblast and osteoclast activity by regulating specific transcription factors.

    DOI: 10.3390/molecules23071517

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  • Bioinspired Mineralization Using Chondrocyte Membrane Nanofragments Reviewed International journal

    Emilio Satoshi Hara, Masahiro Okada, Noriyuki Nagaoka, Takako Hattori, Takuo Kuboki, Takayoshi Nakano, Takuya Matsumoto

    ACS Biomaterials Science & Engineering   4 ( 2 )   617 - 625   2018.2

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    Biomineralization involves complex processes and interactions between organic and inorganic matters, which are controlled in part by the cells. The objectives of this study were, first, to perform a systematic and ultrastructural investigation of the initial mineral formation during secondary ossification center of mouse femur based on material science and biology viewpoint, and then develop novel biomaterials for mineralization based on the in vivo findings. First, we identified the very initial mineral deposition at postnatal day 5 (P5) at the medial side of femur epiphysis by nanocomputed tomography. Initial minerals were found in the surroundings of hypertrophic chondrocytes. Interestingly, histological and immunohistochemical analyses showed that initial mineralization until P6 was based on chondrocyte activity only, i.e., it occurred in the absence of osteoblasts. Moreover, electron microscopy-based ultrastructural analysis showed that cell-secreted matrix vesicles were absent in the early steps of osteoblast-independent endochondral ossification. Instead, chondrocyte membrane nanofragments were found in the fibrous matrix surrounding the hypertrophic chondrocytes. EDS analysis and electron diffraction study indicated that cell membrane nanofragments were not mineralized material, and could be the nucleation site for the newly formed calcospherites. The phospholipids in the cell membrane nanofragments could be a source of phosphate for subsequent calcium phosphate formation, which initially was amorphous, and later transformed into apatite crystals. Finally, artificial cell nanofragments were synthesized from ATDC5 chondrogenic cells, and in vitro assays showed that these nanofragments could promote mineral formation. Taken together, these results indicated that cell membrane nanofragments were the nucleation site for mineral formation, and could potentially be used as material for manipulation of biomineralization.

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  • Chondrocyte burst promotes space for mineral expansion Reviewed International journal

    Emilio Satoshi Hara, Masahiro Okada, Noriyuki Nagaoka, Takako Hattori, Letycia Mary Iida, Takuo Kuboki, Takayoshi Nakano, Takuya Matsumoto

    Integrative Biology   10 ( 1 )   57 - 66   2018

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    Analysis of tissue development from multidisciplinary approaches can result in more integrative biological findings, and can eventually allow the development of more effective bioengineering methods. In this study, we analyzed the initial steps of mineral formation during secondary ossification of mouse femur based on biological and bioengineering approaches. We first found that some chondrocytes burst near the mineralized area. External factors that could trigger chondrocyte burst were then investigated. Chondrocyte burst was shown to be modulated by mechanical and osmotic pressure. A hypotonic solution, as well as mechanical stress, significantly induced chondrocyte burst. We further hypothesized that chondrocyte burst could be associated with space-making for mineral expansion. In fact, ex vivo culture of femur epiphysis in hypotonic conditions, or under mechanical pressure, enhanced mineral formation, compared to normal culture conditions. Additionally, the effect of mechanical pressure on bone formation in vivo was investigated by immobilization of mouse lower limbs to decrease the body pressure onto the joints. The results showed that limb immobilization suppressed bone formation. Together, these results suggest chondrocyte burst as a novel fate of chondrocytes, and that manipulation of chondrocyte burst with external mechano-chemical stimuli could be an additional approach for cartilage and bone tissue engineering.

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  • Generation and Analysis of Cartilage-Specific CCN2 Overexpression in Transgenic Mice

    Takako Hattori, Shinsuke Itoh, Masaharu Takigawa

    Methods in Molecular Biology   391 - 403   2017

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  • Protein Imaging of CCN2 and CCN3 in Living Cells

    Takako Hattori, Mitsuhiro Hoshijima, Masaharu Takigawa

    Methods in Molecular Biology   211 - 215   2017

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  • Production of Recombinant CCN2 Protein in Escherichia coli

    Eriko Aoyama, Takako Hattori, Satoshi Kubota, Masaharu Takigawa

    Methods in Molecular Biology   77 - 84   2017

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  • Protocols for Screening for Binding Partners of CCN Proteins: Yeast Two-Hybrid System

    Mitsuhiro Hoshijima, Takako Hattori, Masaharu Takigawa

    Methods in Molecular Biology   145 - 154   2017

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  • Involvement of multiple CCN family members in platelets that support regeneration of joint tissues. Reviewed International journal

    Chikako Hara, Satoshi Kubota, Takashi Nishida, Miki Hiasa, Takako Hattori, Eriko Aoyama, Yoshinori Moriyama, Hiroshi Kamioka, Masaharu Takigawa

    Modern rheumatology   26 ( 6 )   940 - 949   2016.11

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    OBJECTIVES: Platelet-rich plasma (PRP) has been widely used to enhance the regeneration of damaged joint tissues, such as osteoarthritic and rheumatoid arthritic cartilage. The aim of this study is to clarify the involvement of all of the CCN family proteins that are crucially associated with joint tissue regeneration. METHODS: Cyr61-CTGF-NOV (CCN) family proteins in human platelets and megakaryocytic cells were comprehensively analyzed by Western blotting analysis. Production of CCN family proteins in megakaryocytes in vivo was confirmed by immunofluorescence analysis of mouse bone marrow cells. Effects of CCN family proteins found in platelets on chondrocytes were evaluated by using human chondrocytic HCS-2/8 cells. RESULTS: Inclusion of CCN2, a mesenchymal tissue regenerator, was confirmed. Of note, CCN3, which counteracts CCN2, was newly found to be encapsulated in platelets. Interestingly, these two family members were not detectable in megakaryocytic cells, but their external origins were suggested. Furthermore, we found for the first time CCN5 and CCN1 that inhibits ADAMTS4 in both platelets and megakaryocytes. Finally, application of a CCN family cocktail mimicking platelets onto HCS-2/8 cells enhanced their chondrocytic phenotype. CONCLUSIONS: Multiple inclusion of CCN1, 2 and 3 in platelets was clarified, which supports the harmonized regenerative potential of PRP in joint therapeutics.

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  • Assessment of CCN2 Independent Modules Regenerative Capacity on Osteoarthritis and Further Selecting the Most Suitable Among them as a Potential Therapeutic Drug Reviewed

    Abdelkader Tarek, Aoyama Eriko, Nishida Takashi, Hattori Takako, Janune Danilo, Hara Emilio S, Ono Mitsuaki, Tabata Yasuhiko, Kuboki Takuo, Kubota Satoshi, Takigawa Masaharu

    FASEB JOURNAL   30   2016.4

  • Role of CCN2 in Amino Acid Metabolism of Chondrocytes. Reviewed International journal

    Yurika Murase, Takako Hattori, Eriko Aoyama, Takashi Nishida, Aya Maeda-Uematsu, Harumi Kawaki, Karen M Lyons, Akira Sasaki, Masaharu Takigawa, Satoshi Kubota

    Journal of cellular biochemistry   117 ( 4 )   927 - 37   2016.4

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    CCN2/connective tissue growth factor (CTGF) is a multi-functional molecule that promotes harmonized development and regeneration of cartilage through its matricellular interaction with a variety of extracellular biomolecules. Thus, deficiency in CCN2 supply profoundly affects a variety of cellular activities including basic metabolism. A previous study showed that the expression of a number of ribosomal protein genes was markedly enhanced in Ccn2-null chondrocytes. Therefore, in this study, we analyzed the impact of CCN2 on amino acid and protein metabolism in chondrocytes. Comparative metabolome analysis of the amino acids in Ccn2-null and wild-type mouse chondrocytes revealed stable decreases in the cellular levels of all of the essential amino acids. Unexpectedly, uptake of such amino acids was rather enhanced in Ccn2-null chondrocytes, and the addition of exogenous CCN2 to human chondrocytic cells resulted in decreased amino acid uptake. However, as expected, amino acid consumption by protein synthesis was also accelerated in Ccn2-null chondrocytes. Furthermore, we newly found that expression of two genes encoding two glycolytic enzymes, as well as the previously reported Eno1 gene, was repressed in those cells. Considering the impaired glycolysis and retained mitochondrial membrane potential in Ccn2-null chondrocytes, these findings suggest that Ccn2 deficiency induces amino acid shortage in chondrocytes by accelerated amino acid consumption through protein synthesis and acquisition of aerobic energy. Interestingly, CCN2 was found to capture such free amino acids in vitro. Under physiological conditions, CCN2 may be regulating the levels of free amino acids in the extracellular matrix of cartilage.

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  • Sorcin Expression in the Epiphyseal Growth Plates of Mice Reviewed

    Mariko Kawai, Ning Liu, Takako Hattori, Yo-Hei Kataoka, Masaharu Takigawa, Satoshi Kubota, Toshio Yamamoto, Kiyoshi Ohura

    JOURNAL OF HARD TISSUE BIOLOGY   25 ( 1 )   57 - 61   2016.1

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    Sorcin is a small calcium-binding protein that is widely expressed in many tissues. Sorcin regulates cardiac myocyte apoptosis by modulating mitochondrial Ca2+ cycling and regulates fibroblast cell cycling and apoptosis via Ca2+ signaling through the endoplasmic reticulum (ER). During endochondral ossification, some chondrocytes undergo apoptosis after their terminal differentiation; however, Sorcin's expression in these cells has not been characterized. Here we examined Sorcin's gene expression in the chondrocytes derived from mouse growth plate by reverse transcription PCR (RT-PCR), and its protein localization in the chondrocytes of femoral growth plate using immunohistochemistry. Sorcin protein was detected in the chondrocytes, and was particularly abundant in the cytoplasm and nuclei of proliferative zone chondrocytes and in the nuclei of hypertrophic chondrocytes. Apoptotic analysis of the growth plate revealed that many of the hypertrophic chondrocytes undergo the DNA fragmentation. We report for the first time the localization of Sorcin in the epiphyseal growth plate in which one of the apoptotic phenomenon was detected.

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  • Identification of transactivation-responsive DNA-binding protein 43 (TARDBP43; TDP-43) as a novel factor for TNF-alpha expression upon lipopolysaccharide stimulation in human monocytes Reviewed

    H. Murata, T. Hattori, H. Maeda, S. Takashiba, M. Takigawa, J. Kido, T. Nagata

    JOURNAL OF PERIODONTAL RESEARCH   50 ( 4 )   452 - 460   2015.8

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    Background and ObjectiveTumor necrosis factor alpha (TNF-) is a major cytokine implicated in various inflammatory diseases. The nature of the nuclear factors associated with human TNF- gene regulation is not well elucidated. We previously identified a novel region located from -550 to -487 in human TNF- promoter that did not contain the reported binding sites for nuclear factor kappa B (NF-B) but showed lipopolysaccharide (LPS)-induced transcriptional activity. The purpose of this study is to identify novel factors that bind to the promoter region and regulate TNF- expression.
    Material and MethodsTo identify DNA-binding proteins that bound to the target region of TNF- promoter, a cDNA library from LPS-stimulated human monocytic cell line THP-1 was screened using a yeast one-hybrid system. Cellular localizations of the DNA-binding protein in the cells were examined by subcellular immunocytochemistry. Nuclear amounts of the protein in LPS-stimulated THP-1 cells were identified by western blot analysis. Expression of mRNA of the protein in the cells was quantified by real-time polymerase chain reaction. Electrophoretic mobility shift assays were performed to confirm the DNA-binding profile. Overexpression of the protein and knockdown of the gene were also performed to investigate the role for TNF- expression.
    ResultsSeveral candidates were identified from the cDNA library and transactivation-responsive DNA-binding protein 43 (TARDBP43; TDP-43) was focused on. Western blot analysis revealed that nuclear TDP-43 protein was increased in the LPS-stimulated THP-1 cells. Expression of TDP-43 mRNA was already enhanced before TNF- induction by LPS. Electrophoretic mobility shift assay analysis showed that nuclear extracts obtained by overexpressing FLAG-tagged TDP-43 bound to the -550 to -487 TNF- promoter fragments. Overexpression of TDP-43 in THP-1 cells resulted in an increase of TNF- expression. Knockdown of TDP-43 in THP-1 cells downregulated TNF- expression.
    ConclusionWe identified TDP-43 as one of the novel TNF- factors and found that it bound to the LPS-responsive element in the TNF- promoter to increase TNF- expression.

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  • Dual pathways to endochondral osteoblasts: a novel chondrocyte-derived osteoprogenitor cell identified in hypertrophic cartilage Reviewed International journal

    Jung Park, Matthias Gebhardt, Svitlana Golovchenko, Francesc Perez-Branguli, Takako Hattori, Christine Hartmann, Xin Zhou, Benoit deCrombrugghe, Michael Stock, Holm Schneider, Klaus von der Mark

    BIOLOGY OPEN   4 ( 5 )   608 - 621   2015.5

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    According to the general understanding, the chondrocyte lineage terminates with the elimination of late hypertrophic cells by apoptosis in the growth plate. However, recent cell tracking studies have shown that murine hypertrophic chondrocytes can survive beyond "terminal'' differentiation and give rise to a progeny of osteoblasts participating in endochondral bone formation. The question how chondrocytes convert into osteoblasts, however, remained open. Following the cell fate of hypertrophic chondrocytes by genetic lineage tracing using BACCol10;Cre induced YFP-reporter gene expression we show that a progeny of Col10Cre-reporter labelled osteoprogenitor cells and osteoblasts appears in the primary spongiosa and participates - depending on the developmental stage - substantially in trabecular, endosteal, and cortical bone formation. YFP+ trabecular and endosteal cells isolated by FACS expressed Col1a1, osteocalcin and runx2, thus confirming their osteogenic phenotype. In searching for transitory cells between hypertrophic chondrocytes and trabecular osteoblasts we identified by confocal microscopy a novel, small YFP(+)Osx(+) cell type with mitotic activity in the lower hypertrophic zone at the chondro-osseous junction. When isolated from growth plates by fractional enzymatic digestion, these cells termed CDOP (chondrocyte-derived osteoprogenitor) cells expressed bone typical genes and differentiated into osteoblasts in vitro. We propose the Col10Cre-labeled CDOP cells mark the initiation point of a second pathway giving rise to endochondral osteoblasts, alternative to perichondrium derived osteoprogenitor cells. These findings add to current concepts of chondrocyte-osteocyte lineages and give new insight into the complex cartilage-bone transition process in the growth plate.

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  • Exosomes mediate intercellular transfer of pro-fibrogenic connective tissue growth factor (CCN2) between hepatic stellate cells, the principal fibrotic cells in the liver Reviewed International journal

    Alyssa Charrier, Ruju Chen, Li Chen, Sherri Kemper, Takako Hattori, Masaharu Takigawa, David R. Brigstock

    SURGERY   156 ( 3 )   548 - 555   2014.9

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    Background. Fibrogenic pathways in the liver are principally regulated by hepatic stellate cells (HSC), which produce and respond to fibrotic mediators such as connective tissue growth factor (CCN2). The aim of this study was to determine whether CCN2 is shuttled between HSC in membranous nanovesicles, or "exosomes."
    Methods. Exosomes were incubated with HSC after isolation from conditioned medium of control or CCN2-green fluorescent protein (GFP)-transfected primary mouse HSC or human LX-2 HSC. Some exosomes were stained fluorescently with PKH26. HSC co-culture experiments were performed in the presence of GW4869 exosome inhibitor. CCN2 or CCN2-GFP were evaluated by quantitative real-time polymerase. chain reaction or Western blot.
    Results. HSC-derived exosomes contained CCN2 or CCN2 mRNA, each of which increased in concentration during HSC activation or after transfection of HSC with CCN2-GFP. Exosomes, stained with either PKH26 or purified from CCN2-GFP transfected cells, were taken up by activated or quiescent HSC resulting in CCN2-GFP delivery, as shown by their direct addition to recipient cells or by the GW4869-dependency of donor HSC.
    Conclusion. CCN2 is packaged into secreted, nano-sized exosomes that mediate its intercellular transfer between HSC. Exosomal CCN2 may amplify or fine tune fibrogenic signaling and, in conjunction with other exosome constituents, may have utility as a noninvasive biomarker to assess hepatic fibrosis.

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  • Connective tissue growth factor (CCN2) and microRNA-21 are components of a positive feedback loop in pancreatic stellate cells (PSC) during chronic pancreatitis and are exported in PSC-derived exosomes Reviewed International journal

    Alyssa Charrier, Ruju Chen, Li Chen, Sherri Kemper, Takako Hattori, Masaharu Takigawa, David R. Brigstock

    JOURNAL OF CELL COMMUNICATION AND SIGNALING   8 ( 2 )   147 - 156   2014.6

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    Pancreatitis is an inflammatory condition of the pancreas which, in its chronic form, involves tissue destruction, exocrine and endocrine insufficiency, increased risk of pancreatic cancer, and an extensive fibrotic pathology which is due to unrelenting collagen deposition by pancreatic stellate cells (PSC). In response to noxious agents such as alcohol-excessive consumption of which is a major cause of pancreatitis in the West-normally quiescent PSC undergo a phenotypic and functional transition to activated myofibroblasts which produce and deposit collagen at high levels. This process is regulated by connective tissue growth factor (CCN2), expression of which is highly up-regulated in activated PSC. We show that CCN2 production by activated PSC is associated with enhanced expression of microRNA-21 (miR-21) which was detected at high levels in activated PSC in a murine model of alcoholic chronic pancreatitis. A positive feedback loop between CCN2 and miR-21 was identified that resulted in enhancement of their respective expression as well as that of collagen alpha 1(I). Both miR-21 and CCN2 mRNA were present in PSC-derived exosomes, which were characterized as 50-150 nm CD9-positive nanovesicles. Exosomes from CCN2-GFP- or miR-21-GFP-transfected PSC were taken up by other PSC cultures, as shown by direct fluorescence or qRT-PCR for GFP. Collectively these studies establish miR-21 and CCN2 as participants in a positive feedback loop during PSC activation and as components of the molecular payload in PSC-derived exosomes that can be delivered to other PSC. Thus interactions between cellular or exosomal miR-21 and CCN2 represent novel aspects of fibrogenic regulation in PSC. Summary Chronic injury in the pancreas is associated with fibrotic pathology which is driven in large part by CCN2-dependent collagen production in pancreatic stellate cells. This study shows that CCN2 up-regulation in PSC is associated with increased expression of miR-21 which, in turn, is able to stimulate CCN2 expression further via a positive feedback loop. Additionally miR-21 and CCN2 were identified in PSC-derived exosomes which effected their delivery to other PSC. The cellular and exosomal miR-21-CCN2 axis is a novel component in PSC fibrogenic signaling.

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  • CCN2 as a Novel Molecule Supporting Energy Metabolism of Chondrocytes Reviewed International journal

    Aya Maeda-Uematsu, Satoshi Kubota, Harumi Kawaki, Kazumi Kawata, Yoshiaki Miyake, Takako Hattori, Takashi Nishida, Norifumi Moritani, Karen M. Lyons, Seiji Iida, Masaharu Takigawa

    JOURNAL OF CELLULAR BIOCHEMISTRY   115 ( 5 )   854 - 865   2014.5

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    CCN2/connective tissue growth factor (CTGF) is a unique molecule that promotes both chondrocytic differentiation and proliferation through its matricellular interaction with a number of extracellular biomolecules. This apparently contradictory functional property of CCN2 suggests its certain role in basic cellular activities such as energy metabolism, which is required for both proliferation and differentiation. Comparative metabolomic analysis of costal chondrocytes isolated from wild-type and Ccn2-null mice revealed overall impaired metabolism in the latter. Among the numerous metabolites analyzed, stable reduction in the intracellular level of ATP, GTP, CTP, or UTP was observed, indicating a profound role of CCN2 in energy metabolism. Particularly, the cellular level of ATP was decreased by more than 50% in the Ccn2-null chondrocytes. The addition of recombinant CCN2 (rCCN2) to cultured Ccn2-null chondrocytes partly redeemed the cellular ATP level attenuated by Ccn2 deletion. Next, in order to investigate the mechanistic background that mediates the reduction in ATP level in these Ccn2-null chondrocytes, we performed transcriptome analysis. As a result, several metabolism-associated genes were found to have been up-regulated or down-regulated in the mutant mice. Up-regulation of a number of ribosomal protein genes was observed upon Ccn2 deletion, whereas a few genes required for aerobic and anaerobic ATP production were down-regulated in the Ccn2-null chondrocytes. Among such genes, reduction in the expression of the enolase 1 gene was of particular note. These findings uncover a novel functional role of CCN2 as a metabolic supporter in the growth-plate chondrocytes, which is required for skeletogenesis in mammals. J. Cell. Biochem. 115: 854-865, 2014. (c) 2013 Wiley Periodicals, Inc.

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  • The regenerative effects of CCN2 independent modules on chondrocytes in vitro and osteoarthritis models in vivo Reviewed International journal

    El Kader, Tarek Abd, Kubota Satoshi, Nishida Takashi, Hattori Takako, Aoyama Eriko, Janune Danilo, Hara Emilio S, Ono Mitsuaki, Tabata Yasuhiko, Kuboki Takuo, Takigawa Masaharu

    Bone   59   180 - 188   2014

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    The role of CCN family proteins has been proven to be of extreme importance in the process of cartilage development and endochondral ossification. The second member, CCN2, consists of 4 conserved modules that interact with a number of cofactors to display multiple functions. Although the potentially therapeutic effect of intact CCN2 on cartilage regeneration has been indicated by a number of studies, the regenerative effect of independent modules comprising CCN2 has never been evaluated before. This study aims to discover a more robust and effective CCN2 derivative to induce regeneration through assessing the effect of CCN2 independent modules on regeneration in vitro and in vivo, in comparison to the full length CCN2. In vitro evaluation using human chondrocytic cells showed a remarkable enhancing effect of several single modules on the gene expression of cartilaginous extracellular matrix components; whereas combinations of 2 or 3 modules rather diminished such effects. Interestingly, combination of all 4 modules redeemed the effect of intact CCN2 in vitro. Suspecting the re-assembly of the 4 modules, interaction among the modules was examined by surface plasmon resonance analysis. However, the results did not support the possible formation of a tetramodular complex. Next, the thrombospondin 1 type 1 repeat module (TSP1), which was found most promising in the experiments in vitro, and the combination of 4 modules were forwarded further to in vivo confirmation using 2 rat osteoarthritis (OA) models. As a result, TSP1 displayed more prominent regenerative effects than intact CCN2 on damaged cartilage. Unexpectedly, the combination of 4 modules showed limited effects in vivo. These results indicate the utility of TSP1 in the regenerative therapeutics of OA. Possible molecular mechanism that enables conditional reconstruction of CCN2 by 4 modules is discussed as well. (C) 2013 Elsevier Inc. All rights reserved.

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  • E6-AP/UBE3A Protein Acts as a Ubiquitin Ligase toward SOX9 Protein Reviewed International journal

    Takako Hattori, Tetsuya Kishino, Shelley Stephen, Heidi Eberspaecher, Sayumi Maki, Masaharu Takigawa, Benoit de Crombrugghe, Hideyo Yasuda

    JOURNAL OF BIOLOGICAL CHEMISTRY   288 ( 49 )   35138 - 35148   2013.12

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    Background: Although the ubiquitin-proteasome pathway is thought to regulate the level of SOX9, the ubiquitin ligase involved has not yet been determined. Results: E6-AP/UBE3A was found to bind and ubiquitinate SOX9. Conclusion: E6-AP/UBE3A functions as a ubiquitin ligase toward SOX9 both in vitro and in vivo. Significance: These data provide the regulatory mechanism of the SOX9 level in chondrocytes by ubiquitin ligase.
    SOX9 is a transcription factor that acts as a key regulator at various stages of cartilage differentiation. There is ample evidence that intracellular SOX9 protein levels are tightly regulated both by sumoylation and by degradation through the ubiquitin-proteasome pathway. Using a proteomics approach, here we report the identification of a SOX9-binding protein, E6-AP/UBE3A, that may act as a ubiquitin ligase toward Sox9. E6-AP bound SOX9 through the region consisting mostly of its high mobility group domain in vitro. In nuclear lysates, FLAG-tagged E6-AP coprecipitated with Sox9 and its high mobility group domain. This finding was estimated using nuclear lysates from a chondrocytic cell line that endogenously expresses E6-AP and SOX9. Accordingly, ectopically expressed E6-AP and SOX9 colocalized in the nucleus. We show that E6-AP ubiquitinates SOX9 in vitro and in vivo and that SOX9 levels are enhanced after addition of the proteasome inhibitor bortezomib. Similar, siRNA knockdown of E6-AP and the E2 ligase Ubc9 increased cellular SOX9 amounts, supporting the notion that SOX9 may be ubiquitinated in hypertrophic chondrocytes by E6-AP and degraded by proteasomes. This is in accordance with the distribution of SOX9 levels, which are high in proliferating and prehypertrophic chondrocytes but low in hypertrophic chondrocytes, whereas E6-AP levels are high in hypertrophic chondrocytes and low in prehypertrophic chondrocytes. Furthermore, E6-AP-deficient mice showed SOX9 accumulation in chondrocytes and the brain. These findings support the concept that E6-AP regulates SOX9 levels in developing cartilage by acting as a ubiquitin ligase.

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  • CCN Family Member 2/Connective Tissue Growth Factor (CCN2/CTGF) Has Anti-Aging Effects That Protect Articular Cartilage from Age-Related Degenerative Changes Reviewed International journal

    Shinsuke Itoh, Takako Hattori, Nao Tomita, Eriko Aoyama, Yasutaka Yutani, Takashi Yamashiro, Masaharu Takigawa

    PLOS ONE   8 ( 8 )   e71156   2013.8

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    To examine the role of connective tissue growth factor CCN2/CTGF (CCN2) in the maintenance of the articular cartilaginous phenotype, we analyzed knee joints from aging transgenic mice (TG) overexpressing CCN2 driven by the Col2a1 promoter. Knee joints from 3-, 14-, 40-, and 60-day-old and 5-, 12-, 18-, 21-, and 24-month-old littermates were analyzed. Ccn2-LacZ transgene expression in articular cartilage was followed by X-gal staining until 5 months of age. Overexpression of CCN2 protein was confirmed through all ages in TG articular cartilage and in growth plates. Radiographic analysis of knee joints showed a narrowing joint space and other features of osteoarthritis in 50% of WT, but not in any of the TG mice. Transgenic articular cartilage showed enhanced toluidine blue and safranin-O staining as well as chondrocyte proliferation but reduced staining for type X and I collagen and MMP-13 as compared with those parameters for WT cartilage. Staining for aggrecan neoepitope, a marker of aggrecan degradation in WT articular cartilage, increased at 5 and 12 months, but disappeared at 24 months due to loss of cartilage; whereas it was reduced in TG articular cartilage after 12 months. Expression of cartilage genes and MMPs under cyclic tension stress (CTS) was measured by using primary cultures of chondrocytes obtained from wild-type (WT) rib cartilage and TG or WT epiphyseal cartilage. CTS applied to primary cultures of mock-transfected rib chondrocytes from WT cartilage and WT epiphyseal cartilage induced expression of Col1a1, ColXa1, Mmp-13, and Mmp-9 mRNAs; however, their levels were not affected in CCN2-overexpressing chondrocytes and TG epiphyseal cartilage. In conclusion, cartilage-specific overexpression of CCN2 during the developmental and growth periods reduced age-related changes in articular cartilage. Thus CCN2 may play a role as an anti-aging factor by stabilizing articular cartilage.

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  • Deletion of beta catenin in hypertrophic growth plate chondrocytes impairs trabecular bone formation. Reviewed International journal

    Svitlana Golovchenko, Takako Hattori, Christine Hartmann, Matthias Gebhardt, Sonja Gebhard, Andreas Hess, Friederike Pausch, Britta Schlund, Klaus von der Mark

    Bone   55 ( 1 )   102 - 12   2013.7

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    In order to elucidate the role of β-catenin in hypertrophic cartilage zone of the growth plate, we deleted the β-catenin gene ctnnb1specifically from hypertrophic chondrocytes by mating ctnnb1(fl/fl) mice with BAC-Col10a1-Cre-deleter mice. Surprisingly, this resulted in a significant reduction of subchondral trabecular bone formation in BACCol10Cre; ctnnb1(Δ/Δ) (referred to as Cat-ko) mice, although Cre expression was restricted to hypertrophic chondrocytes. The size of the Col10a1 positive hypertrophic zone was normal, but qRT-PCR revealed reduced expression of Mmp13, and Vegfa in Cat-ko hypertrophic chondrocytes, indicating impaired terminal differentiation. Immunohistological and in situ hybridization analysis revealed the substantial deficiency of collagen I positive mature osteoblasts, but equal levels of osterix-positive cells in the subchondral bone marrow space of Cat-ko mice, indicating that the supply of osteoblast precursor cells was not reduced. The fact that in Cat-ko mice subchondral trabeculae were lacking including their calcified cartilage core indicated a strongly enhanced osteoclast activity. In fact, TRAP staining as well as in situ hybridization analysis of Mmp9 expression revealed denser occupation of the cartilage erosion zone with enlarged osteoclasts as compared to the control growth plate, suggesting increased RANKL or reduced osteoprotegerin (Opg) activity in this zone. This notion was confirmed by qRT-PCR analysis of mRNA extracted from cultured hypertrophic chondrocytes or from whole epiphyses, showing increased Rankl mRNA levels in Cat-ko as compared to control chondrocytes, whereas changes in OPG levels were not significant. These results indicate that β-catenin levels in hypertrophic chondrocytes play a key role in regulating osteoclast activity and trabecular bone formation at the cartilage-bone interface by controlling RANKL expression in hypertrophic chondrocytes.

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  • Cartilage-Specific Over-Expression of CCN Family Member 2/Connective Tissue Growth Factor (CCN2/CTGF) Stimulates Insulin-Like Growth Factor Expression and Bone Growth Reviewed International journal

    Nao Tomita, Takako Hattori, Shinsuke Itoh, Eriko Aoyama, Mayumi Yao, Takashi Yamashiro, Masaharu Takigawa

    PLoS ONE   8 ( 3 )   e59226   2013.3

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    Previously we showed that CCN family member 2/connective tissue growth factor (CCN2) promotes the proliferation, differentiation, and maturation of growth cartilage cells in vitro. To elucidate the specific role and molecular mechanism of CCN2 in cartilage development in vivo, in the present study we generated transgenic mice overexpressing CCN2 and analyzed them with respect to cartilage and bone development. Transgenic mice were generated expressing a ccn2/lacZ fusion gene in cartilage under the control of the 6 kb-Col2a1-enhancer/promoter. Changes in cartilage and bone development were analyzed histologically and immunohistologically and also by micro CT. Primary chondrocytes as well as limb bud mesenchymal cells were cultured and analyzed for changes in expression of cartilage-related genes, and non-transgenic chondrocytes were treated in culture with recombinant CCN2. Newborn transgenic mice showed extended length of their long bones, increased content of proteoglycans and collagen II accumulation. Micro-CT analysis of transgenic bones indicated increases in bone thickness and mineral density. Chondrocyte proliferation was enhanced in the transgenic cartilage. In in vitro short-term cultures of transgenic chondrocytes, the expression of col2a1, aggrecan and ccn2 genes was substantially enhanced
    and in long-term cultures the expression levels of these genes were further enhanced. Also, in vitro chondrogenesis was strongly enhanced. IGF-I and IGF-II mRNA levels were elevated in transgenic chondrocytes, and treatment of non-transgenic chondrocytes with recombinant CCN2 stimulated the expression of these mRNA. The addition of CCN2 to non-transgenic chondrocytes induced the phosphorylation of IGFR, and ccn2-overexpressing chondrocytes showed enhanced phosphorylation of IGFR. Our data indicates that the observed effects of CCN2 may be mediated in part by CCN2-induced overexpression of IGF-I and IGF-II. These findings indicate that CCN2-overexpression in transgenic mice accelerated the endochondral ossification processes, resulting in increased length of their long bones. Our results also indicate the possible involvement of locally enhanced IGF-I or IGF-II in this extended bone growth. © 2013 Tomita et al.

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  • Anti-fibrotic effect of CCN3 accompanied by altered gene expression profile of the CCN family Reviewed International journal

    Tarek Abd El Kader, Satoshi Kubota, Danilo Janune, Takashi Nishida, Takako Hattori, Eriko Aoyama, Bernard Perbal, Takuo Kuboki, Masaharu Takigawa

    Journal of Cell Communication and Signaling   7 ( 1 )   11 - 18   2013.3

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    CCN family proteins 2 and 3 (CCN2 and CCN3) belong to the CCN family of proteins, all having a high level of structural similarity. It is widely known that CCN2 is a profibrotic molecule that mediates the development of fibrotic disorders in many different tissues and organs. In contrast, CCN3 has been recently suggested to act as an anti-fibrotic factor in several tissues. This CCN3 action was shown earlier to be exerted by the repression of the CCN2 gene expression in kidney tissue, whereas different findings were obtained for liver cells. Thus, the molecular action of CCN3 yielding its anti-fibrotic effect is still controversial. Here, using a general model of fibrosis, we evaluated the effect of CCN3 overexpression on the gene expression of all of the CCN family members, as well as on that of fibrotic marker genes. As a result, repression of CCN2 gene expression was modest, while type I collagen and α-smooth muscle actin gene expression was prominently repressed. Interestingly, not only CCN2, but also CCN4 gene expression showed a decrease upon CCN3 overexpression. These findings indicate that fibrotic gene induction is under the control of a complex molecular network conducted by CCN family members functioning together. © 2012 The International CCN Society.

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  • Novel chondrogenic and chondroprotective effects of the natural compound harmine. Reviewed

    Hara ES, Ono M, Kubota S, Sonoyama W, Oida Y, Hattori T, Nishida T, Furumatsu T, Ozaki T, Takigawa M, Kuboki T.

    Biochimie   95 ( 2 )   374 - 381   2013.2

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  • Novel chondrogenic and chondroprotective effects of the natural compound harmine International journal

    Emilio Satoshi Hara, Mitsuaki Ono, Satoshi Kubota, Wataru Sonoyama, Yasutaka Oida, Takako Hattori, Takashi Nishida, Takayuki Furumatsu, Toshifumi Ozaki, Masaharu Takigawa, Takuo Kuboki

    Biochimie   95 ( 2 )   374 - 381   2013.2

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    A significant number of natural compounds have been shown to regulate the behavior of the cells, in collaboration with cellular proteins. CCN2/connective tissue growth factor (CTGF) has been reported to have essential roles in cartilage development, chondrocyte proliferation and differentiation as well as regulation of the extracellular matrix metabolism. Previous studies demonstrated the capability of CCN2 to regenerate surgical defects in articular cartilage of rat knee. Also, transgenic mice over-expressing cartilage-specific CCN2 were shown to be more resistant to aging-related cartilage degradation. We hypothesized that small molecules that induce CCN2 in chondrocytes could be novel candidates to increase the resistance to aging-related cartilage degradation, or even to correct cartilage degenerative changes incurred in OA. Therefore, this study screened a compound library and identified the β-carboline alkaloid harmine as a novel inducer of CCN2 in human chondrocytic HCS-2/8 cells and osteoarthritic articular chondrocytes. Harmine increased the expression of the cartilage markers aggrecan and COL2α1, as well as that of the master regulator of chondrogenesis, SOX-9. Moreover, harmine notably induced chondrogenesis of prechondrocytic ATDC5 cells in micromass cultures. The chondroprotective effect of harmine was investigated under inflammatory condition by stimulation with TNFα, and harmine was shown to ameliorate TNFα-induced decrease in expression of CCN2 and cartilage markers. These findings uncover novel chondrogenic effects of harmine and indicate harmine as a potential drug for prevention and/or repair of cartilage degradation.

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  • The CCN2-inducer harmine promotes chondrogenesis and protects against TNFα-induced ablation of chondrocytic phenotype Reviewed

    Hara, E.S, M. Ono, S. Kubota, W. Sonoyama, Y. Oida, T. Hattori, T. Nishida, T. Furumatsu, T. Ozaki, M. Takigawa, T. Kuboki

    Biochimie   95   374 - 381   2013

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  • Roles of heterotypic CCN2/CTGF-CCN3/NOV and homotypic CCN2-CCN2 interactions in expression of the differentiated phenotype of chondrocytes Reviewed International journal

    Mitsuhiro Hoshijima, Takako Hattori, Eriko Aoyama, Takashi Nishida, Takashi Yamashiro, Masaharu Takigawa

    FEBS JOURNAL   279 ( 19 )   3584 - 3597   2012.10

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    To identify proteins that regulate CCN2 activity, we carried out GAL4-based yeast two-hybrid screening with a cDNA library derived from a chondrocytic cell line, HCS-2/8. CCN2/CTGF and CCN3/NOV polypeptides were picked up as CCN2-binding proteins, and CCN2CCN2 and CCN2CCN3 binding domains were identified. Direct binding between CCN2 and CCN3 was confirmed by coimmunoprecipitation in vitro and in vivo and surface plasmon resonance, and the calculated dissociation constants (Kd) were 1.17 x 10-9 m for CCN2 and CCN2, and 1.95 x 10-9 m for CCN2 and CCN3. Ectopically overexpressed green fluorescent proteinCCN2 and HaloCCN3 in COS7 cells colocalized, as determined by direct fluorescence analysis. We present evidence that CCN2CCN3 interactions modulated CCN2 activity such as enhancement of ACAN and col2a1 expression. Curiously, CCN2 enhanced, whereas CCN3 inhibited, the expression of aggrecan and col2a1 mRNA in HCS-2/8 cells, and combined treatment with CCN2 and CCN3 abolished the inhibitory effect of CCN3. These effects were neutralized with an antibody against the von Willebrand factor type C domain of CCN2 (11H3). This antibody diminished the binding between CCN2 and CCN2, but enhanced that between CCN3 and CCN2. Our results suggest that CCN2 could form homotypic and heterotypic dimers with CCN2 and CCN3, respectively. Strengthening the binding between CCN2 and CCN3 with the 11H3 antibody had an enhancing effect on aggrecan expression in chondrocytes, suggesting that CCN2 had an antagonizing effect by binding to CCN3.

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  • The Wnt antagonist Wif-1 interacts with CTGF and inhibits CTGF activity Reviewed International journal

    Cordula Surmann-Schmitt, Takako Sasaki, Takako Hattori, Nicole Eitzinger, Georg Schett, Klaus Von der Mark, Michael Stock

    JOURNAL OF CELLULAR PHYSIOLOGY   227 ( 5 )   2207 - 2216   2012.5

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    Wnt inhibitory factor 1 (Wif-1) is a secreted antagonist of Wnt signalling. We recently demonstrated that this molecule is expressed predominantly in superficial layers of epiphyseal cartilage but also in bone and tendon. Moreover, we showed that Wif-1 is capable of binding to several cartilage-related Wnt ligands and interferes with Wnt3a-dependent Wnt signalling in chondrogenic cells. Here we provide evidence that the biological function of Wif-1 may not be confined to the modulation of Wnt signalling but appears to include the regulation of other signalling pathways. Thus, we show that Wif-1 physically binds to connective tissue growth factor (CTGF/CCN2) in vitro, predominantly by interaction with the C-terminal cysteine knot domain of CTGF. In vivo such an interaction appears also likely since the expression patterns of these two secreted proteins overlap in peripheral zones of epiphyseal cartilage. In chondrocytes CTGF has been shown to induce the expression of cartilage matrix genes such as aggrecan (Acan) and collagen2a1 (Col2a1). In this study we demonstrate that Wif-1 is capable to interfere with CTGF-dependent induction of Acan and Col2a1 gene expression in primary murine chondrocytes. Conversely, CTGF does not interfere with Wif-1-dependent inhibition of Wnt signalling. These results indicate that Wif-1 may be a multifunctional modulator of signalling pathways in the cartilage compartment. J. Cell. Physiol. 227: 2207-2216, 2012. (C) 2011 Wiley Periodicals, Inc.

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  • In Vivo Three-Dimensional Kinematics of the Cervical Spine During Head Rotation in Patients With Cervical Spondylosis Reviewed International journal

    Yukitaka Nagamoto, Takahiro Ishii, Hironobu Sakaura, Motoki Iwasaki, Hisao Moritomo, Masafumi Kashii, Takako Hattori, Hideki Yoshikawa, Kazuomi Sugamoto

    SPINE   36 ( 10 )   778 - 783   2011.5

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    Study Design. Kinematics of the cervical spine during head rotation was investigated using 3-dimensional (3D) magnetic resonance imaging (MRI) in patients with cervical spondylosis (CS).
    Objective. To demonstrate in vivo 3D kinematics of the spondylotic cervical spine during head rotation.
    Summary of Background Data. Several in vivo studies have identified kinematic differences between normal and spondylotic subjects, but only two-dimensional flexion/extension motion has been investigated. Differences of in vivo 3D cervical motion during head rotation between normal and spondylotic subjects have yet to be clarified.
    Methods. Ten healthy volunteers (control group) and 15 patients with CS (CS group) underwent 3D MRI of the cervical spine with the head rotated to 5 positions (neutral, +/- 45 degrees and +/- maximal head rotation). Relative motions of the cervical spine were calculated by automatically superimposing a segmented 3D MRI of the vertebra in the neutral position over images for each position using volume registration. The 3D motions of adjacent vertebra were represented with 6 degrees of freedom by Euler angles and translations on the coordinate system.
    Results. Compared with the control group, the CS group showed significantly decreased mean axial rotation and mean coupled lateral bending at C5-C6 and C6-C7 and significantly increased mean coupled lateral bending at C2-C3 and C3-C4, although both the groups showed the same pattern of coupled motions.
    Conclusion. The in vivo 3D kinematics of the spondylotic cervical spine during head rotation was accurately depicted and compared with those of healthy cervical spines for the first time.

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  • The dimerization domain of SOX9 is required for transcription activation of a chondrocyte-specific chromatin DNA template. International journal

    Françoise Coustry, Chun-do Oh, Takako Hattori, Sankar N Maity, Benoit de Crombrugghe, Hideyo Yasuda

    Nucleic acids research   38 ( 18 )   6018 - 28   2010.10

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    Mutations in SOX9, a gene essential for chondrocyte differentiation cause the human disease campomelic dysplasia (CD). To understand how SOX9 activates transcription, we characterized the DNA binding and cell-free transcription ability of wild-type SOX9 and a dimerization domain SOX9 mutant. Whereas formation of monomeric mutant SOX9-DNA complex increased linearly with increasing SOX9 concentrations, formation of a wild-type SOX9-DNA dimeric complex increased more slowly suggesting a more sigmoidal-type progression. Stability of SOX9-DNA complexes, however, was unaffected by the dimerization mutation. Both wild-type and mutant SOX9 activated transcription of a naked Col2a1 DNA template. However, after nucleosomal assembly, only wild-type and not the mutant was able to remodel chromatin and activate transcription of this template. Using a cell line, in which the Col2a1 vector was stably integrated, no differences were seen in the interactions of wild-type and mutant SOX9 with the chromatin of the Col2a1 vector using ChIP. However, the mutant was unable to activate transcription in agreement with in vitro results. We hypothesize that the SOX9 dimerization domain is necessary to remodel the Col2a1 chromatin in order to allow transcription to take place. These results further clarify the mechanism that accounts for CD in patients harboring SOX9 dimerization domain mutations.

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  • SOX9 is a major negative regulator of cartilage vascularization, bone marrow formation and endochondral ossification Reviewed International journal

    Takako Hattori, Catharina Mueller, Sonja Gebhard, Eva Bauer, Friederike Pausch, Britta Schlund, Michael R. Boesl, Andreas Hess, Cordula Surmann-Schmitt, Helga von der Mark, Benoit de Crombrugghe, Klaus von der Mark

    DEVELOPMENT   137 ( 6 )   901 - 911   2010.3

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    SOX9 is a transcription factor of the SRY family that regulates sex determination, cartilage development and numerous other developmental events. In the foetal growth plate, Sox9 is highly expressed in chondrocytes of the proliferating and prehypertrophic zone but declines abruptly in the hypertrophic zone, suggesting that Sox9 downregulation in hypertrophic chondrocytes might be a necessary step to initiate cartilage-bone transition in the growth plate. In order to test this hypothesis, we generated transgenic mice misexpressing Sox9 in hypertrophic chondrocytes under the control of a BAC-Col10a1 promoter. The transgenic offspring showed an almost complete lack of bone marrow in newborns, owing to strongly retarded vascular invasion into hypertrophic cartilage and impaired cartilage resorption, resulting in delayed endochondral bone formation associated with reduced bone growth. In situ hybridization analysis revealed high levels of Sox9 misexpression in hypertrophic chondrocytes but deficiencies of Vegfa, Mmp13, RANKL and osteopontin expression in the non-resorbed hypertrophic cartilage, indicating that Sox9 misexpression in hypertrophic chondrocytes inhibits their terminal differentiation. Searching for the molecular mechanism of SOX9-induced inhibition of cartilage vascularization, we discovered that SOX9 is able to directly suppress Vegfa expression by binding to SRY sites in the Vegfa gene. Postnatally, bone marrow formation and cartilage resorption in transgenic offspring are resumed by massive invasion of capillaries through the cortical bone shaft, similar to secondary ossification. These findings imply that downregulation of Sox9 in the hypertrophic zone of the normal growth plate is essential for allowing vascular invasion, bone marrow formation and endochondral ossification.

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  • N-terminal domains of CCN family 2/connective tissue growth factor bind to aggrecan Reviewed International journal

    Eriko Aoyama, Takako Hattori, Mitsuhiro Hoshijima, Daisuke Araki, Takashi Nishida, Satoshi Kubota, Masaharu Takigawa

    BIOCHEMICAL JOURNAL   420 ( 3 )   413 - 420   2009.6

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    CCN2/CTGF (CCN family 2/connective tissue growth factor) is a multi-cellular protein with a broad range of activities. It modulates many cellular functions, including proliferation, migration, adhesion and extracellular matrix production, and it is thus involved in many biological and pathological processes. In particular, CCN2/CTGF is essential for normal skeletal development. To identify CCN2/CTGF-interactive proteins capable of modulating its action in cartilage, we carried Out a yeast two-hybrid screening using CCN2/CTGF peptide as a bait and a cDNA library from a chondrocytic cell line, HCS-2/8. In the present paper, we report the identification of aggrecan, which is a major proteoglycan of the extracellular matrix in cartilage, its a CCN2/CTGF-binding protein. Among the four domains of CCN2/CTGF, the IGFBP [IGF (insulin-like growth factor)-binding protein-like] and/or VWC (von Willebrand factor type C) domains had a direct interaction with aggrecan in a yeast two-hybrid assay. The results of a solid-phase-binding assay using aggrecan-coated plates also showed binding to recombinant CCN2/CTGF in a dose-dependent manner. rIGFBP (recombinant IGFBP) and rVWC (recombinant VWC) module peptides had stronger binding to aggrecan compared with rTSP1 (recombinant thrombospondin type I repeat) and rCT (recombinant C-terminal cystine knot) module peptides. SPR (surface plasmon resonance) analysis showed the direct interaction between the CCN2/CTGF and aggrecan. and ectopically overexpressed CCN2/CTGF and AgG3 (G3 domain of aggrecan) confirmed their binding in vivo. Indirect immunofluorescence analysis indicated that CCN2/CTGF was extracellularly co-localized with aggrecan on HCS-2/8 cells. The rIGFBP-rVWC peptide effectively enhanced tire production and release of aggrecan compared with the rTSP-rCT peptide in chondrocytes. These results indicate that CCN2/CTGF binds to aggrecan through its N-terminal IGFBP and VWC Modules. and this binding may be related to the CCN2/CTGF-enhanced production and secretion of aggrecan by chondrocytes.

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  • The expression and crucial roles of BMP signaling in development of smooth muscle progenitor cells in the mouse embryonic gut. International journal

    Shigeko Torihashi, Takako Hattori, Hirotaka Hasegawa, Masaaki Kurahashi, Takunori Ogaeri, Toyoshi Fujimoto

    Differentiation; research in biological diversity   77 ( 3 )   277 - 89   2009.3

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    Bone morphogenetic protein (BMP) signaling is essential for normal development of the gastrointestinal (GI) tract. BMPs also play multiple roles in vascular smooth muscle cells; however, the BMP signaling in the development of the GI musculature remains to be clarified. We investigated the expression of BMPs and their receptors in mouse embryonic GI tracts by immunohistochemistry and in situ hybridization. We demonstrated that BMP2, BMP receptor Ib and BMP receptor II were expressed in the smooth muscle progenitors from E12 to E13 for the first time. BMP signaling on smooth muscle differentiation was examined by implantation of agarose beads soaked with BMPs in the in vitro developmental model that is gut-like structures from mouse embryonic stem (ES) cells. BMP2 rather than BMP4 beads enhanced smooth muscle differentiation, and increased gut-like structures showing spontaneous contractions and expressing intensive alpha-smooth muscle actin immunoreactivity. This increase was confirmed by up-regulation of SM22 mRNA shown by real-time PCR. By addition of noggin beads or noggin to the medium at BMP2 bead implantation, the ratio of contractive gut-like structures decreased. Implantation of BMP2 beads at EB7 (EB--embryoid bodies) (corresponding to E12 or E13 of mouse embryo) showed the highest effects and up-regulation of transcription factors msx-1 after 24h. This increase was blocked by noggin, and msx-1 decreased to almost the control level after 60 h. BMP2 beads at EB7 increased platelet-derived growth factor-A (PDGF-A) in the differentiating smooth muscle cells. We have recently reported that PDGF-A is expressed in the developing inner circular smooth muscle and is crucial for the longitudinal smooth muscle differentiation. Taken together, BMP signaling was expressed for a short window in the smooth muscle progenitors and the signal, especially BMP2, plays an essential role in smooth muscle differentiation in cooperation with PDGF signaling.

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  • Specific expression of Cre recombinase in hypertrophic cartilage under the control of a BAC-Col10a1 promoter. International journal

    Sonja Gebhard, Takako Hattori, Eva Bauer, Britta Schlund, Michael R Bösl, Benoit de Crombrugghe, Klaus von der Mark

    Matrix biology : journal of the International Society for Matrix Biology   27 ( 8 )   693 - 9   2008.10

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    Previously we have shown that insertion of a LacZ reporter gene into the Col10a1 gene in the context of a bacterial artificial chromosome (BAC) drives strong and specific expression of LacZ in hypertrophic cartilage of transgenic mice [Gebhard S., Hattori T., Bauer E., Bosl M.R., Schlund B., Poschl E., Adam N., de Crombrugghe B., von der Mark K., 2007 Histochem. Cell Biol. 19 127:183-194]. BAC constructs in transgenic reporter mouse lines control efficient and specific LacZ expression in hypertrophic chondrocytes under the complete Col10a1 promoter. Here we report on the generation of Col10a1-specific Cre deleter mice using a BAC recombineering technique based on homologous recombination in E. coli. Sixteen BAC-Col10-Cre transgenic lines were generated containing between 1 and 5 copies of the BAC-Col10-Cre gene. All lines tested so far expressed Cre specifically in hypertrophic chondrocytes of E16.5 and P1 growth plates of long bones, ribs, vertebrae and sternum as examined by crossing with ROSA26 reporter mice. Cre activity was detected as early as E13.5 when hypertrophic cartilage develops in the diaphysis of femur and humerus. The data confirm that expression of Cre under the control of the complete BAC-Col10a1 promoter occurs with high efficiency and specificity in hypertrophic chondrocytes. The BAC-Col10-Cre lines should thus provide a valuable tool to get further insight into the role of genes involved in endochondral ossification by allowing their specific deletion in the hypertrophic zone of the growth plate.

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  • CCN family 2/connective tissue growth factor (CCN2/CTGF) stimulates proliferation and differentiation of auricular chondrocytes

    T. Fujisawa, T. Hattori, M. Ono, J. Uehara, S. Kubota, T. Kuboki, M. Takigawa

    Osteoarthritis and Cartilage   16 ( 7 )   787 - 795   2008.7

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    Objectives: CCN family 2/connective tissue growth factor (CCN2/CTGF) is an atypical growth factor for growth plate chondrocytes. It plays an important role in their proliferation and differentiation in vitro, but does not stimulate hypertrophy or calcification of articular chondrocytes. We herein report for the first time that CCN2/CTGF promotes growth and differentiation of auricular chondrocytes and maintains their molecular phenotype in vitro and in vivo. Methods: Auricular chondrocytes were isolated from rabbit auricular cartilage by trypsin-collagenase treatment, and treated with human recombinant CCN2/CTGF or infected with adenovirus harboring the ccn2/ctgf gene. Cell proliferation was measured by [3H] thymidine incorporation and MTS assay, and changes in gene expression of auricular chondrocyte markers were monitored by real-time polymerase chain reaction, Northern hybridization, and histological analysis. For in vivo studies, auricular chondrocytes were cultured as pellets and implanted subcutaneously after treatment of recombinant human CCN2/CTGF. Ectopically formed cartilage was subjected to histological analysis. Cell death was monitored by in situ TUNEL analysis. Results: CCN2/CTGF stimulated proliferation, differentiation and synthesis of elastin and proteoglycans of rabbit primary auricular chondrocytes in a dose-dependent manner. CCN2/CTGF caused a 2.5-fold increase in the expression of elastin in comparison to the control, resulting in enhanced deposition of elastin fibers in a monolayer culture of auricular chondrocytes. Mineralization was not induced; in contrast, CCN2/CTGF stimulated expression of matrix gla protein which is known to impair mineralization. Furthermore, pretreatment of pellets of auricular chondrocytes with CCN2/CTGF and subcutaneous implantation significantly enhanced the growth of ectopic auricular cartilage pieces expressing phenotypic markers of auricular chondrocytes including type II and X collagen. Notably, chondrocyte apoptosis was impaired by CCN2/CTGF. Conclusions: These findings show that CCN2/CTGF may be a suitable agent for promoting differentiation and growth of auricular chondrocytes, while preventing mineralization and apoptosis, and suggests that CCN2/CTGF may be useful for the repair or reconstruction of elastic cartilage. © 2007 Osteoarthritis Research Society International.

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  • Radiological study of joint destruction patterns in rheumatoid flatfoot Reviewed International journal

    Takako Hattori, Jun Hashimoto, Tetsuya Tomita, Takashi Kitamura, Hideki Yoshikawa, Kazuomi Sugamoto

    CLINICAL RHEUMATOLOGY   27 ( 6 )   733 - 737   2008.6

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    The purpose of this study was to clarify variations in patterns of flattening in rheumatoid hindfoot. Out of 232 outpatients with rheumatoid arthritis treated at our hospital from 2001 to 2003, we studied lateral radiographs of feet of 216 patients (423 weight-bearing views). We measured the medial arch angle (MAA) and talar angle (TA) and compared the alignment of the talonavicular joint-sagittal plane of each foot. We also evaluated the relationship between the severity of flattening and inclination of the talus and performed cluster analysis. Three groups were clustered by MAA and TA. In group I, joints were normal or close to normal. In group II, both talonavicular and subtalar joints were affected. In group III, talonavicular joints were minimally affected, and the subtalar joints were primarily affected. Groups II and III were thought to be a different pattern of flattening. The present results suggest that there are at least two patterns of flattening in rheumatoid hindfoot.

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  • Transcriptional regulation of chondrogenesis by coactivator Tip60 via chromatin association with Sox9 and Sox5. International journal

    Takako Hattori, Francoise Coustry, Shelley Stephens, Heidi Eberspaecher, Masaharu Takigawa, Hideyo Yasuda, Benoit de Crombrugghe

    Nucleic acids research   36 ( 9 )   3011 - 24   2008.5

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    Sox9 is a transcription factor of the SRY family required for several steps of chondrogenesis. It activates the expression of various chondrocyte-specific genes, but the mechanisms and role of cofactors involved in Sox9-regulated gene transcription are not fully understood. Here, we report on the characterization of a Tat interactive protein-60 (Tip60) as Sox9-associated protein identified in a yeast two-hybrid screen. Both in vitro and in vivo assays confirmed the specificity of interactions between Sox9 and Tip60 including the existence of an endogenous complex containing both polypeptides in chondrocytes. Gel shift assays showed the presence of a complex containing Sox9, Tip60 and the DNA of an enhancer region of the Col2a1 promoter. Reporter assays using a Col2a1 promoter with multimerized Col2a1 Sox9-binding sites indicated that Tip60 enhanced the transcriptional activity of Sox9. A larger Col2a1 promoter showed that Tip60 increased the activity of this promoter in the presence of both Sox9 and Sox5. Ectopic expression of Sox9 and transient-cotransfection with Tip60 in COS7 cells showed a more diffuse subnuclear colocalization, suggesting changes in the chromatin structure. Chromatin immunoprecipitation assays showed that Tip60, Sox9 and Sox5 associated with the same Col2a1 enhancer region. Consistent with a role of Tip60 in chondrogenesis, addition of Tip60 siRNA to limb-bud micromass cultures delayed chondrocyte differention. Tip60 enhances acetylation of Sox9 mainly through K61, 253, 398 residues; however, the K61/253/398A mutant of Sox9 still exhibited enhanced transcriptional activity by Tip60. Our results support the hypothesis that Tip60 is a coactivator of Sox9 in chondrocytes.

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  • CCN family 2 / Connective tissue growth factor (CCN2/CTGF) stimulates proliferation and differentiation of auricular chondrocytes. Reviewed

    Fujisawa T, Hattori T, Ono M, Uehara J, Kubota S, Kuboki T, Takigawa M

    Osteoarthritis and Cartilage   16   787 - 795   2008

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  • Radiographic study of joint destruction patterns in the rheumatoid elbow. International journal

    Takashi Kitamura, Jun Hashimoto, Tsuyoshi Murase, Tetsuya Tomita, Takako Hattori, Hideki Yoshikawa, Kazuomi Sugamoto

    Clinical rheumatology   26 ( 4 )   515 - 9   2007.4

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    Knowledge of the pattern of joint destruction is important for planning the therapeutic approach to rheumatoid arthritis (RA) of the elbow. Accordingly, we carried out a large-scale radiographic study with the objective of elucidating the joint destruction pattern in rheumatoid elbows. From 2001 through 2003, we examined and took plain X-rays of both elbows of 193 RA patients (i.e., 386 elbows), consisting of 18 men and 175 women, with a mean age of 57.0 years. Radiographic images of the elbow joints were used to classify the degree of bone loss in various zones on the elbow joint surface into four grades of severity, and joint destruction was compared between the left and right elbows. In addition, correlation in the extent of bone loss between each of the zones of the same elbow and differences in the extent of bone loss were analyzed statistically. The results showed direct correlations for destruction of the elbow joint surface among the zones for the left and right elbow joints and in the same elbow joint. However, more severe destruction was observed on the radial side of the humeral trochlea, and it was surmised that destruction of the elbow joint must begin at that site and gradually spread mediolaterally. In addition, in the same elbow joint, the correlation in the degree of bone loss between the trochlea of humerus and the trochlear notch was especially strong, indicating that the bone destruction at both sites represented mirror lesions. We conclude that when performing radiographic diagnosis of the joint damage in the rheumatoid elbow, knowledge of this pattern of joint destruction will be useful for assessing whether there is joint destruction in the initial stage and for deciding the therapeutic approach.

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  • BAC constructs in transgenic reporter mouse lines control efficient and specific LacZ expression in hypertrophic chondrocytes under the complete Col10a1 promoter. Reviewed International journal

    Sonja Gebhard, Takako Hattori, Eva Bauer, Michael R Bösl, Britta Schlund, Ernst Pöschl, Nadia Adam, Benoit de Crombrugghe, Klaus von der Mark

    Histochemistry and cell biology   127 ( 2 )   183 - 94   2007.2

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    During endochondral ossification hypertrophic chondrocytes in the growth plate of fetal long bones, ribs and vertebrae play a key role in preparing growth plate cartilage for replacement by bone. In order to establish a reporter gene mouse to facilitate functional analysis of genes expressed in hypertrophic chondrocytes in this process, Col10a1- BAC reporter gene mouse lines were established expressing LacZ specifically in hypertrophic cartilage under the control of the complete Col10a1 gene. For this purpose, a bacterial artificial chromosome (BAC RP23-192A7) containing the entire murine Col10a1 gene together with 200 kb flanking sequences was modified by inserting a LacZ-Neo cassette into the second exon of Col10a1 by homologous recombination in E. coli. Transgenic mice containing between one and seven transgene copies were generated by injection of the purified BAC-Col10a1- lLacZ DNA. X-gal staining of newborns and embryos revealed strong and robust LacZ activity exclusively in hypertrophic cartilage of the fetal and neonatal skeleton of the transgenic offspring. This indicates that expression of the reporter gene in its proper genomic context in the BAC Col10a1 environment is independent of the integration site and reflects authentic Col10a1 expression in vivo. The Col10a1 specific BAC recombination vector described here will enable the specific analysis of effector gene functions in hypertrophic cartilage during skeletal development, endochondral ossification, and fracture callus healing.

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  • Twisted gastrulation modulates bone morphogenetic protein-induced collagen II and X expression in chondrocytes in vitro and in vivo. Reviewed International journal

    Martina Schmidl, Nadia Adam, Cordula Surmann-Schmitt, Takako Hattori, Michael Stock, Uwe Dietz, Benoit de Crombrugghe, Ernst Pöschl, Klaus von der Mark

    The Journal of biological chemistry   281 ( 42 )   31790 - 800   2006.10

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    Twisted gastrulation (TSG) is an extracellular modulator of bone morphogenetic protein (BMP) activity and regulates dorsoventral axis formation in early Drosophila and Xenopus development. Studies on tsg-deficient mice also indicated a role of this protein in skeletal growth, but the mechanism of TSG activity in this process has not yet been investigated. Here we show for the first time by in situ hybridization and immunohistochemistry that TSG is strongly expressed in bovine and mouse growth plate cartilage as well as in fetal ribs, vertebral cartilage, and cartilage anlagen of the skull. Furthermore we provide evidence that TSG is directly involved in BMP-regulated chondrocyte differentiation and maturation. In vitro, TSG impaired the dose-dependent BMP-2 stimulation of collagen II and X expression in cultures of MC615 chondrocytes and primary mouse chondrocytes. In the presence of chordin, a BMP antagonist, the inhibitory effect of TSG was further enhanced. TSG also inhibited BMP-2-stimulated phosphorylation of Smad factors in chondrocytes, confirming the role of TSG as a modulator of BMP signaling. For analysis of TSG functions in cartilage development in vivo, the gene was overexpressed in transgenic mice under the control of the cartilage-specific Col2a1 promoter. As a result, Col10a1 expression was significantly reduced in the growth plates of transgenic embryos and newborns in comparison with wild type littermates as shown by in situ hybridization and by real time PCR analysis. The data suggest that TSG is an important modulator of BMP-regulated cartilage development and chondrocyte differentiation.

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  • [Autoantigen and molecular chaperone in rheumatoid arthritis--their roles in metabolism of chondrocytes]. Reviewed

    Takako Hattori, Masaharu Takigawa

    Clinical calcium   16 ( 9 )   1553 - 56   2006.9

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    The endoplasmic reticulum chaperone; heat shock protein/rheumatoid arthritis-related antigen (HSP47/RA-A47), in addition to its important intercellular functions for collagen maturation and secretion, has chondrocytes-destructive roles such as induction of endoplasmic reticulum (ER)-stress and metabolic gene expressions result in apoptosis when HSP47/RA-A47 is downregulated. Extracellular HSP47/RA-A47 may act as an autoantigen, but also regulate autoimmune inflammation. It is, therefore, a potential new biologic therapy for rheumatoid arthritis.

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  • Interactions between PIAS proteins and SOX9 result in an increase in the cellular concentrations of SOX9 Reviewed International journal

    T Hattori, H Eberspaecher, JF Lu, R Zhang, T Nishida, T Kahyo, H Yasuda, B de Crombrugghe

    JOURNAL OF BIOLOGICAL CHEMISTRY   281 ( 20 )   14417 - 14428   2006.5

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    We have identified PIAS1 (protein inhibitor of activated STAT-1), -3, -x alpha, and -x beta as SOX9-associated polypeptides using the Gal4-based yeast two-hybrid system and a cDNA library derived from a chondrocytic cell line. These PIAS proteins were shown to interact directly with SOX9 in two-hybrid, co-immunoprecipitation, and electrophoretic mobility shift assays. SOX9 was sumoylated in cotransfection experiments with COS-7 cells using PIAS and SUMO-1 (small ubiquitin-like modifier-1) expression vectors. SOX9 was also sumoylated in vitro by PIAS proteins in the presence of SUMO-1, the SUMO-activating enzyme, and the SUMO-conjugating enzyme. In COS-7 cells, PIAS proteins stimulated the SOX9-dependent transcriptional activity of a Col2a1 promoter-enhancer reporter. This increase in reporter activity was paralleled by an increase in the cellular levels of SOX9. Cotransfection with a SUMO-expressing vector further enhanced the transcriptional activity of this SOX9-dependent Col2a1 reporter in COS-7 cells, and this additional activation was inhibited in the presence of either SUMO-1 mutants or PIAS RING domain mutants or by coexpression of a desumoylation enzyme. Immunofluorescence microscopy of SOX9-transfected COS-7cells showed that the subnuclear distribution of SOX9 became more diffuse in the presence of PIAS1 and SUMO-1. Our results suggest that, by controlling the cellular concentrations of SOX9, PIAS proteins and sumoylation may be part of a major regulatory system of SOX9 functions.

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  • CT domain of CCN2/CTGF directly interacts with fibronectin and enhances cell adhesion of chondrocytes through integrin alpha 5 beta 1 Reviewed International journal

    M Hoshijima, T Hattori, M Inoue, D Araki, H Hanagata, A Miyauchi, M Takigawa

    FEBS LETTERS   580 ( 5 )   1376 - 1382   2006.2

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    Searching for CCN family protein 2/connective tissue growth factor (CCN2/CTGF) interactive proteins by yeast-two-hybrid screening, we identified fibronectin 1 gene product as a major binding partner of CCN2/CTGF in the chondrosarcoma-derived chondrocytic cell line HCS-2/8. Only the CT domain of CCN2/CTGF bound directly to fibronectin (FN). CCN2/CTGF and its CT domain enhanced the adhesion of HCS-2/8 cells to FN in a dose-dependent manner. The CCN2/CTGF-enhancing effect on cell adhesion to FN was abolished by a blocking antibody against alpha 5 beta 1 integrin (alpha 5 beta 1), but not by one against anti-alpha v beta 3 integrin. These findings suggest for the first time that CCN2/CTGF enhances chondrocyte adhesion to FN through direct interaction of its C-terminal CT domain with FN, and that alpha 5 beta 1 is involved in this adhesion. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

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  • Downregulation of rheumatoid arthritis-related antigen RA-A47 (HSP47/colligin-2) in chondrocytic cell lines induces apoptosis and cell-surface expression of RA-A47 in association with CD9. Reviewed International journal

    Takako Hattori, Klaus von der Mark, Harumi Kawaki, Yasutaka Yutani, Satoshi Kubota, Tohru Nakanishi, Heidi Eberspaecher, Benoit de Crombrugghe, Masaharu Takigawa

    Journal of cellular physiology   202 ( 1 )   191 - 204   2005.1

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    Previously, we showed that gene expression of the rheumatoid arthritis-related antigen RA-A47, which is identical to human heat shock protein (HSP)47, was downregulated in chondrocytes by inflammatory cytokines such as TNFalpha. Associated with this phenomenon, RA-A47 appeared on the cell surface concomitant with upregulation of metabolic factors related to cartilage destruction. The upregulation of the metabolic factors could be achieved by downregulation of RA-A47 expression with ra-a47-specific anti-sense oligonucleotide. Here, we show that the enhanced surface expression of RA-A47 on a chondrocytic cell line, HCS-2/8 was also a direct result of RA-A47 downregulation by ra-a47 anti-sense oligonucleotide, independent of the cytokine effects. Moreover, cell-surface expression of CD9, a beta1 integrin-associated transmembrane protein that is involved in cell adhesion and cell motility events, was enhanced in the ra-a47 anti-sense oligonucleotide-treated cells. The CD9 was colocalized with RA-A47 on the cell surface, where it may have affected integrin signaling. Furthermore, Annexin-V binding to the cell surface and the level of a number of apoptosis-related genes including caspase-9 were increased after ra-a47 anti-sense oligonucleotide treatment, suggesting that enhanced surface expression of RA-A47 and CD9 may be initiating apoptosis. Differential screening using a cDNA gene array showed induction of metallothionein-III and chemokine receptor CXCR4 and of factors of the Notch signaling pathway by the anti-sense treatment, but not by TNFalpha. Thus, here we show for the first time an alternative mechanism of inducing apoptosis by downregulating molecular chaperones, independent of the action of TNFalpha. The surface-exposed RA-A47 may induce autoantibodies and inflammatory reactions in autoimmune disease situations such as rheumatoid arthritis.

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  • Differentiation of Human Bone Marrow Mesenchymal Stem Cells to Chondrocytes for Construction of Three-dimensional Cartilage Tissue. International journal

    Chikayoshi Matsuda, Mutsumi Takagi, Takako Hattori, Shigeyuki Wakitani, Toshiomi Yoshida

    Cytotechnology   47 ( 1-3 )   11 - 7   2005.1

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    A differentiation method of human bone marrow mesenchymal stem cells (MSCs) to chondrocytes was developed for the construction of a three-dimensional (3D) cartilage tissue. The adhesive cells, which were isolated from a human bone marrow aspirate were embedded in type I collagen in a poly-L: -lactate-glycolic acid copolymer (PLGA) mesh and cultivated for 4 week together with growth factors. The degree of cellular differentiation was estimated by quantitative RT-PCR of aggrecan and type II collagen mRNAs and by staining with Safranin O. The 3D culture showed a higher degree of differentiation even without growth factors than the conventional pellet culture with growth factors, namely, dexamethasone and transforming growth factor (TGF)-beta 3. The 3D culture for 2 week with the combined addition of dexamethasone, TGF-beta 3, and insulin-like growth factor (IGF)-I reached a 30% expression of aggrecan mRNA compared with that in primary human chondrocytes, while the aggrecan mRNA expression in the conventional pellet culture was less than 2%. The sequential two-step differentiation cultivation, during which the cells were cultivated in 3D for 1 week after the conventional two-dimensional (2D) culture for 1 week, could markedly accelerate the expression of aggrecan mRNA compared with the 3D cultivation for 2 week.

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  • Effect of Subcultivation of Human Bone Marrow Mesenchymal Stem on their Capacities for Chondrogenesis, Supporting Hematopoiesis, and Telomea Length. International journal

    Masaki Nakahara, Mutsumi Takagi, Takako Hattori, Shigeyuki Wakitani, Toshiomi Yoshida

    Cytotechnology   47 ( 1-3 )   19 - 27   2005.1

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    Effects of subcultivation of human bone marrow mesenchymal stem cells on their capacities for chondrogenesis and supporting hematopoiesis, and telomea length were investigated. Mesenchymal stem cells were isolated from human bone marrow aspirates and subcultivated several times at 37 degrees C under a 5% CO(2) atmosphere employing DMEM medium containing 10% FCS up to the 20th population doubling level (PDL). The ratio of CD45(-) CD105(+) cells among these cells slightly increased as PDL increased. However, there was no marked change in the chondrogenic capacity of these cells, which was confirmed by expression assay of aggrecan mRNA and Safranin O staining after pellet cell cultivation. The change in capacity to support hematopoiesis of cord blood cells was not observed among cells with various PDLs. On the other hand, telomere length markedly decreased as PDL increased at a higher rate than that at which telomere length of primary mesenchymal stem cells decreased as the age of donor increased.

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  • A highly conserved enhancer in mammalian type X collagen genes drives high levels of tissue-specific expression in hypertrophic cartilage in vitro and in vivo. Reviewed International journal

    Sonja Gebhard, Ernst Pöschl, Silvia Riemer, Eva Bauer, Takako Hattori, Heidi Eberspaecher, Zhaoping Zhang, Veronique Lefebvre, Benoit de Crombrugghe, Klaus von der Mark

    Matrix biology : journal of the International Society for Matrix Biology   23 ( 5 )   309 - 22   2004.8

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    Previously we have identified a cis-acting regulatory domain in the human type X collagen gene upstream of the transcription start site which acts as a strong enhancer in hypertrophic, but not in resting chondrocytes. Here we show that this enhancer is highly conserved also in the murine and bovine Col10a1 genes, but not found in the known promoter sequences of chicken Col10a1. It contains a functionally active AP-1 site (TPA Responsive Element, TRE) which is essential for the high transcriptional activity of the COL10A1 enhancer in transiently transfected hypertrophic chondrocytes. Gel-shift experiments with nuclear extracts of hypertrophic chondrocytes revealed FosB and Fra-1 as candidates regulating AP-1 factors binding to the TRE site. In fact, coexpression of FosB and Fra-1 in reporter gene assays greatly stimulated transcriptional activity of enhancer bearing reporter genes. Quantitative analysis of AP-1 factor mRNA levels in distinct fractions of fetal bovine epiphyseal chondrocytes by real-time PCR confirmed significant levels of FosB and Fra-1 mRNA besides other AP-1 factors in hypertrophic chondrocytes. A key role of the enhancer element in regulating tissue-specific expression of the Col10a1 gene was shown by establishing transgenic mouse lines with a reporter gene containing a 4.6 kb murine Col10a1 promoter fragment which included the enhancer, exon 1, part of exon 2 and the first intron. Reporter gene expression was seen exclusively in hypertrophic cartilages in the growth plates of long bones, ribs, vertebrae, sternum and mandibles of 17.5-18.5 dpc embryos, confirming that the 4.6 kb promoter is able to drive specific expression of Col10a1 in hypertrophic cartilage. These established transgenic lines should facilitate the genetic analysis of regulatory pathways of chondrocyte maturation and Col10a1 gene expression in the future.

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  • Novel enzyme-linked immunosorbent assay systems for the quantitative analysis of connective tissue growth factor (CTGF/Hcs24/CCN2): Detection of HTLV-I tax-induced CTGF from a human carcinoma cell line Reviewed International journal

    H Kawaki, S Kubota, M Minato, NH Moritani, T Hattori, H Hanagata, M Kubota, A Miyauchi, T Nakanishi, M Takigawa

    DNA AND CELL BIOLOGY   22 ( 10 )   641 - 648   2003.10

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    Connective tissue growth factor/hypertrophic chondrocyte-specific gene product 24 (CTGF/Hcs24/CCN2) is known as a multifunctional growth factor. It stimulates proliferation, migration, and extracellular matrix production of mesenchymal cells, and is highly expressed in hypertrophic chondrocytes. In this study, we constructed useful ELISA systems for the analysis of CTGF and its modular fragments. For this objective we prepared four different antihuman CTGF monoclonal antibodies. One, specific for the VWC module, was utilized as the detecting antibody, and the other three, recognizing CT, IGFBP, and VWC modules, respectively, were employed as capture antibodies. Then we established three novel quantitative analysis systems for CTGF. The first system recognizing CT and VWC modules was useful to measure full-length CTGF with improved sensitivity. Utilizing this system, we found significant enhancement of CTGF production from a human carcinoma cell line transduced by HTLV-I tax gene, where the finding indicates the possible involvement of Tax in carcinogenesis. The second system, seeing IGFBP and VWC modules, could quantify not only CTGF, but also may be useful to analyze processed N-terminal fragments. The third system, utilizing capture and detection antibodies against the VWC module, was able to quantify the VWC module only, while it did not recognize full-length CTGF. Since CTGF is actually processed into subfragments, and functional assignment of each module is of interest, these systems are expected to contribute to the progress of CTGF investigations.

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  • Downregulation of a rheumatoid arthritis-related antigen (RA-A47) by ra-a47 antisense oligonucleotides induces inflammatory factors in chondrocytes. Reviewed International journal

    Takako Hattori, Harumi Kawaki, Satoshi Kubota, Yasutaka Yutani, Benoit de Crombrugghe, Klaus von der Mark, Masaharu Takigawa

    Journal of cellular physiology   197 ( 1 )   94 - 102   2003.10

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    Previously we have shown that the expression of RA-A47 (rheumatoid arthritis-related antigen) which is identical to HSP47, a collagen-binding chaperon, is downregulated in chondrocytes by tumor necrosis factor alpha (TNFalpha). RA-A47 was also found on the surface of chondrocytes where it is recognized as an antigen in the serum of rheumatoid arthritis (RA) patients. Its translocation to the cell surface from endoplasmic reticulum membrane where it is normally located was also enhanced by TNFalpha. To understand the significance of RA-A47 downregulation in chondrocytes independent from other effects of TNFalpha, we used an antisense oligonucleotide approach and investigated the effect of this treatment on the expression of molecules related to matrix degradation and production of growth factors for chondrocytic, endothelial, and synovial cells. Here we show that treatment of rabbit chondrocyes and human chondrosarcoma cells HCS-2/8 by ra-a47 antisense S-oligonucleotides significantly reduced the expression of ra-a47 both at mRNA and protein level. Interestingly, this TNFalpha-independent RA-A47 downregulation was associated with a strong induction of matrix metalloproteinase (MMP)-9 mRNA and inducible NO synthase (iNOS) mRNA. The induction of active-type MMP-9 was further detected by gelatin zymography. Under the same conditions, the release of basic fibroblast growth factor (bFGF) and connective tissue growth factor (CTGF) from HCS-2/8 cells into the conditioned medium (CM) was strongly enhanced. These effects were not a result of TNFalpha upregulation, since the ra-a47 antisense oligonucleotide treatment did not enhance TNFalpha synthesis. These observations indicate that downregulation of RA-A47 induces TNFalpha-independent cartilage-degrading pathways involving iNOS and MMP-9. Furthermore, the stimulation of bFGF and CTGF release from chondrocytes may stimulate the proliferation of adjacent endothelial and/or synovial cells.

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  • A repetitive, steady mouth opening induced an osteoarthritis-like lesion in the rabbit temporomandibular joint Reviewed

    T Fujisawa, T Kuboki, T Kasai, W Sonoyama, S Kojima, J Uehara, C Komori, H Yatani, Hattori, I, M Takigawa

    JOURNAL OF DENTAL RESEARCH   82 ( 9 )   731 - 735   2003.9

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    Although excessive mechanical stress is assumed to be one of the factors contributing to pathogenesis of temporomandibular joint (TMJ) osteoarthritis (OA), no pure mechanical-stress-induced OA model has been developed without surgical manipulation or puncture of the joint cavity. The purpose of this study was to establish a genuine mechanical-stress-induced OA model of the rabbit TMJ. In the experimental rabbits, repetitive, forced jaw-opening, 3 hrs/day for 5 days, was applied with the use of a general anesthesia protocol. By histological assessment of the TMJ articular tissues, partial eburnation of the articular cartilage, reactive marginal proliferation of the articular cartilage chondrocytes, and nested proliferation of chondrocytes in the subchondral bone area were observed at 7 days after the repetitive, forced-jaw-opening period. These results suggest that the repetitive, forced-jaw-opening protocol without surgical intervention can induce evident OA-like lesions in the rabbit TMJ, and this OA model may greatly contribute to the elucidation of the cartilage degradation mechanism in TMJ OA.

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  • CTGF/Hcs24 interacts with the cytoskeletal protein actin in chondrocytes Reviewed International journal

    G Yosimichi, S Kubota, T Hattori, T Nishida, K Nawachi, T Nakanishi, M Kamada, T Takano-Yamamoto, M Takigawa

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   299 ( 5 )   755 - 761   2002.12

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    Connective tissue growth factor/hypertrophic chondrocyte-specific gene product 24 (CTGF/Hcs24) displays multiple functions in several types of mesenchymal cells, including the promotion of proliferation and differentiation of chondrocytes. Recently, the internalization and intracellular function of CTGF/Hcs24 were indicated as well. In this study, a binding protein for this factor was purified from the cytosolic fraction of human chondrosarcoma-derived chondrocytic cell line (HCS-2/8) by CTGF/Hcs24-affinity chromatography. The apparent molecular weight of the protein was 42 kDa and determination of the internal amino acid sequence revealed this protein to be beta- or gamma-actin. An in vitro competitive binding assay of I-125-labeled recombinant CTGF/Hcs24 with cold-rCTGF/Hcs24 showed that the binding between actin and I-125-CTGF/Hcs24 was specific. Immunoprecipitation analysis also showed that CTGF/Hcs24 bound to actin in HCS-2/8 cells. However, rCTGF/Hcs24 had no effects on the expression level of gamma-actin mRNA or total actin protein. These findings suggest that a significant portion of intracellular CTGF/Hcs24 may regulate certain cell biological events in chondrocytes through the interaction with this particular cytoskeletal protein. (C) 2002 Elsevier Science (USA). All rights reserved.

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  • [Articular cartilage regeneration].

    Takako Hattori, Shigeyuki Wakitani

    Clinical calcium   12 ( 2 )   217 - 21   2002.2

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    The main functions of articular cartilages are load-bearing and reducing friction of the articular surfaces. Because the capacity of articular cartilage to repair is limited, many attempts have been made to repair articular cartilage defects, which include transplantations of various tissues or cells. Within them, autologous cultured chondrocyte or autologous bone marrow mesenchymal cell transplantations are reported to be useful methods to repair articular cartilage defects. Here, we introduce these methods of tissue engineering and gene therapy, which are expected to become new treatments of articular cartilage defects.

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  • CTGF/Hcs24 induces chondrocyte differentiation through a p38 mitogen-activated protein kinase (p38MAPK), and proliferation through a p44/42 MAPK/extracellular-signal regulated kinase (ERK) Reviewed

    G Yosimichi, T Nakanishi, T Nishida, T Hattori, T Takano-Yamamoto, M Takigawa

    EUROPEAN JOURNAL OF BIOCHEMISTRY   268 ( 23 )   6058 - 6065   2001.12

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    Connective tissue growth factor/hypertrophic chondrocyte specific gene product 24 (CTGF/Hcs24) promotes proliferation and differentiation of chondrocytes in culture. We investigated the roles of two major types of mitogen activated protein kinase (MAPK) in the promotion of proliferation and differentiation by CTGF/Hcs24. Here we report the effects of the MAPKK/MEK 1/2 inhibitor, PD098059, and p38 MAPK inhibitor, SB203580, in a human chondrosarcoma-derived chondrocytic cell line (HCS-2/8) and rabbit growth cartilage (RGC) cells treated with CTGF/Hcs24. In the proliferation phase, CTGF/Hcs24 induced a approximate to fivefold increase in the phosphorylation of p44/42 MAPK/ERK and a approximate to twofold increase in that of p38 MAPK in an in vivo kinase assay. These inhibitors of MAPKK and MAPK suppressed phosphorylation of ets-like gene-1 (Elk-1) and nuclear activating transcription factor-2 (Atf-2) induced by CTGF/Hcs24 in a dose-dependent manner, respectively. Western blot analysis showed that phosphorylation of ERK was induced from 30 to 60 min and phosphorylation of p38 MAPK from 10 to 15 min after the addition of CTGF/Hcs24 in confluence HCS-2/8 cells. PD098059 suppressed the DNA synthesis of HCS-2/8 cells and RGC cells, while SB203580 did not. On the other hand, the p38 MAPK inhibitor, SB203580, completely inhibited the CTGF/Hcs24-induced synthesis of proteoglycans in HCS-2/8 cells and RGC cells but the MEK1/2 inhibitor, PD098059, did not. These results suggest that ERK mediates the CTGF/Hcs24-induced proliferation of chondrocytes, and that p38 MAPK mediates the CTGF/Hcs24-induced differentiation of chondrocytes.

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  • Cell-type-specific trans-activation of herpes simplex virus thymidine kinase promoter by the human T-cell leukemia virus type I Tax protein. Reviewed

    Kubota S, Mukudai Y, Hattori T, Eguchi T, Kondo S, Takigawa M

    DNA and cell biology   20 ( 9 )   563 - 568   2001.9

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  • Change in cellular localization of a rheumatoid arthritis-related antigen (RA-A47) with downregulation upon stimulation by inflammatory cytokines in chondrocytes. Reviewed

    Hattori, T, Kubota, S, Yutani Y, Fujisawa T, Nakanishi, T, Takahashi, K, Takigawa M

    J. Cell. Physiol.   186   268 - 281   2001

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  • Regulatory mechanism of human connective tissue growth factor (CTGF/Hcs24) gene expression in a human chondrocytic cell line, HCS-2/8. Reviewed

    Eguchi, T, Kubota, S, Kondo, S, Shimo, T, Hattori, T, Nakanishi, T, Kuboki, T, Yatani, H, Takigawa, M

    J. Biochem.   130   79 - 87   2001

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  • Novel mode of processing and secretion of connective tissue growth factor/ecogenin (CTGF/Hcs24) in chondrocytic HCS-2/8 cells. Reviewed

    Kubota, S, Eguchi, T, Shimo, T, Nishida T, Hattori, T, Kondo, S, Nakanishi, T, Takigawa, M

    Bone   29   155 - 161   2001

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  • Characterization of a Mouse ctgf 3′-UTR Segment That Mediates Repressive Regulation of Gene Expression Reviewed

    Seiji Kondo, Satoshi Kubota, Takanori Eguchi, Takako Hattori, Tohru Nakanishi, Toshio Sugahara, Masaharu Takigawa

    Biochemical and Biophysical Research Communications   278 ( 1 )   119 - 124   2000.11

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    We isolated a small segment of the 3'-untranslated region (3'-UTR) in the mouse connective tissue growth factor (ctgf/fisp12) gene and evaluated its functionality. Comparison of the nucleotide sequences of human and mouse ctgf 3'-UTRs revealed a conserved small segment of 91 bases. The corresponding segments of the 3'-UTRs shared as much as 82.4% homology, whereas the overall homology between the 3'-UTRs was 71.8%. To study the functionality of the conserved segment, the corresponding region of mouse ctgf cDNA was amplified from NIH3T3 cells. When it was fused downstream of a marker gene, it showed remarkable repressive effects on gene expression. The repressive effect of the sense form was more prominent than that of the antisense form. Computer analyses of these sequence predicted stable secondary structures, suggesting that they act at the RNA level. The predicted structures of the sense and antisense forms appeared to be slightly different, which is consistent with the difference in repressive function. These findings defined the conserved small element in the mouse ctgf gene as a potent negative regulator of gene expression, which may act at a posttranscriptional level. (C) 2000 Academic Press.

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  • Shear bond strengths of orthodontic plastic brackets

    G. Guan, T. Takano-Yamamoto, M. Miyamoto, T. Hattori, K. Ishikawa, K. Suzuki

    American journal of orthodontics and dentofacial orthopedics : official publication of the American Association of Orthodontists, its constituent societies, and the American Board of Orthodontics   117 ( 4 )   438 - 443   2000.4

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    The purpose of the present study was to evaluate the shear bond strengths of plastic brackets and the influences of the bracket filler contents on the bonding. The shear bond strengths of 4 plastic brackets (Spirit; Spirit MB; Clear Bracket; Aesthetic-Line) bonded to enamel with 4 orthodontic adhesives (Orthomite Superbond; System 1+; Transbond XT; and Kurasper-F) were compared with the strength of a conventional metal bracket. The findings of this study indicated the following: (1) shear bond strength of the 4 plastic brackets was significantly lower than that of the conventional metal brackets (P <.05), with most of the values ranging from 3 MPa to 6 MPa; (2) when comparing the bond strengths of plastic brackets, Aesthetic-Line had the largest value followed by Spirit MB, Spirit, and Clear Bracket, and when the plastic brackets were bonded with Orthomite Superbond, they showed relatively stronger bond strengths than when bonded with the other adhesives. Clear Bracket showed relatively lower values especially when bonded with System 1+; (3) the application of primer did not increase the durability of the bond strengths when bonding Spirit and Clear brackets; and (4) fillers contained in each plastic bracket ranging from 9.18% to 19. 52% were fairly well distributed and showed the same morphology of a fiber type 10 microm in diameter with different lengths. The filler concentration tended to correlate with the bond strength. The exposed fillers on the bracket base surface may play a more important role in plastic bracket adhesion than the macro-morphology of the base surface.

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  • Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Synovial Fluids of Patients with Temporomandibular Joint Osteoarthritis Reviewed

    Manabu Kanyama, Takuo Kuboki, Shunji Kojima, Takuo Fujisawa, Takako Hattori, Masaharu Takigawa, Atsushi Yamashita

    Journal of Orofacial Pain   14 ( 1 )   20 - 30   2000

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    Aims: Imbalance between matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) may be involved in the breakdown of articular cartilage matrix of the temporomandibular joint (TMJ). Aims: In this study, MMPs, TIMPs, and MMP-1/TIMP-1 complex levels were examined in TMJ synovial fluid samples aspirated from TMJ osteoarthritis (OA) patients (2 males, 8 females
    mean age, 29.7 years) and asymptomatic control subjects (2 males, 8 females
    mean age, 23.6 years) to determine the likelihood of increased proteolytic activity in the OA joints. Methods: The various types of MMPs and TIMPs were detected by Western blotting with monoclonal antibodies and gelatin zymography. The MMP-1/ TIMP-1 complex level was measured by an enzyme-linked immunosorbent assay kit. All aspirates were first analyzed for total protein content and then individually diluted to make the total protein levels equivalent. Results: The mean MMP-1/TIMP-1 complex concentration in the synovial fluids of the OA patients was 3.92 ± 1.39 ng/mL
    this value was significantly lower (P &lt
    0.05) than the value from control subjects (5.46 ± 1.32 ng/mL). Matrix metalloproteinase-1 (52 kDa), MMP-3 (57 kDa), TIMP-1 (28 kDa), and TIMP-2 (26 kDa) were detected in all of the normal and the OA samples. However, MMP-1 (28 kDa), MMP-2 (72 kDa), MMP-3 (45 kDa), and MMP-9 (83 kDa) were detected in higher concentration in the OA samples. Conclusion: These findings suggest a strong association between the OA-active joints and the presence of biologically active forms of known tissue degradation enzymes (MMP-1, MMP-3, and MMP-9).

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  • Novel intracellular effects of human connective tissue growth factor expressed in Cos-7 cells.

    Kubota, S, Hattori, T, Shimo, T, Nakanishi, T, Takigawa, M

    FEBS Letters   474   58 - 62   2000

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  • Identification of an RNA element that confers post-transcriptional repression of connective tissue growth factor/hypertrophic chondrocyte specific 24 (ctgf/hcs24) gene: Similarities to retroviral RNA-protein interactions. Reviewed

    Kubota, S, Kondo, S, Eguchi1, T, Hattori, T, Nakanishi, T, Pomerantz, R.J, Takigawa, M

    Oncogene   19   4773 - 4786   2000

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  • 軟骨由来の慢性関節リウマチ関連抗原RA-A47に関する研究(Study on a rheumatoid arthritis-related antigen (RA-A47) isolated from chondrocytes). Reviewed

    服部高子

    2000

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  • Rheumatoid arthritis-related antigen 47kDa (RA-A47) is a product of colligin-2 and acts as a human HSP47 Reviewed

    T Hattori, K Takahashi, Y Yutani, T Fujisawa, T Nakanishi, M Takigawa

    JOURNAL OF BONE AND MINERAL METABOLISM   18 ( 印刷中 )   323 - 334   2000

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    We previously isolated RA-A47, which is recognized as an antigen of rheumatoid arthritis (RA), from a human chondrosarcoma-derived cell line (HCS-2/8). The N-terminal 21-amino-acid sequence of RA-A47 had 81% homology to the deduced amino acid sequence of the human heat-shock protein (HSP) 47 gene, the colligin gene, and 100% homology to that of the colligin-2 gene. Moreover, as is HSP47, RA-A47 was a heat-inducible collagen-binding protein. To further characterize RA-A47, we isolated ra-a47 cDNA from HCS-2/8 cells and human periodontal ligament fibroblast (HPLF) cells. The isolated ra-a47 cDNAs from both cells were almost the same as that of collipin-2. C-504 and G(505) in the cDNA sequences of both cells and C-598 in the cDNA of HCS-2/8 were different from the corresponding bases of colligin-2 cDNA. These differences were also observed in genomic DNA. colligin cDNA was not isolated. To show that the isolated cDNA encodes RA-A47 protein, it was expressed in Cos-7 cells. The produced protein was 47 kDa and was recognized both with RA sera and antirat HSP47 antibody, indicating that it is RA-A47 and has structural similarity to HSP47. These results taken together with our previous finding show that RA-A47 is the putative colligin-2 gene product and behaves as a human HSP47. Although colligin has been considered the human HSP47 gene, failure to detect the colligin gene and its mRNA suggests that colligin does not exist in human cells and that the HSP47 gene is identical with colligin-2, which encodes RA-A47.

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    Other Link: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2000&ichushi_jid=J04654&link_issn=&doc_id=20001102080004&doc_link_id=10.1007%2Fs007740070004&url=https%3A%2F%2Fdoi.org%2F10.1007%2Fs007740070004&type=Crossref&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00002_2.gif

  • 軟骨細胞様培養細胞株HCS-2/8における慢性関節リウマチ関連抗原RA-A47の炎症性サイトカインによる発現抑制と細胞内局在変化. (Downregulation of a rheumatoid arthritis-related antigen (RA-A47) by stimulation of inflammatory cytokines in chondrocytic cell line, HCS-2/8). Reviewed

    服部高子

    岡山歯学会雑誌   19 ( 2 )   241 - 254   2000

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    ra-a47mRNAにおいてTGFβで発現量が増加し,II型コラーゲン遺伝子(COL2A1)mRNAの発現量の増加と同調していることが観察された.対称的に,腫瘍壊死因子(TNF)α,インターフェロン(IFN)β,インターロイキン(IL)-6等の炎症性サイトカイン刺激によってra-a47mRNAの発現量は減少したが,COL2A1mRNAの発現量は減少せず,むしろ増加することがHCS-2/8で観察された.更に,誘導型一酸化窒素合成酵素(iNOS)mRNA,マトリックスメタロプロテアーゼ(MMP-9)mRNAの発現がTNFα刺激で強く誘導されていることが明らかとなった

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  • Detection of specific antibodies against human cultured chondrosarcoma (HCS-2/8) and osteosarcoma (Saos-2) cells in the serum of patients with osteoarthritis of the temporomandibular joint Reviewed

    T Kuboki, T Hattori, T Mizushima, M Kanyama, T Fujisawa, A Yamashita, M Takigawa

    ARCHIVES OF ORAL BIOLOGY   44 ( 5 )   403 - 414   1999.5

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    To find specific humoral antibodies in sera from patients with temporomandibular joint (TMJ) osteoarthritis (OA), an immortal human chondrocyte (HCS-2/8) and osteoblast (Saos-2) cell line derived from a chondrosarcoma and an osteosarcoma, respectively, were used as source proteins of human antigens. Patients with chronically painful TMJ OA (n = 18) but no other joints symptoms were selected from a consecutive series of patients with temperomandibular disorders and sex-matched asymptomatic controls (n = 8) were also recruited. Cellular proteins of the HCS-2/8 and Saos-2 cells were subjected to Western blotting with the OA and control sera as probes. Band-recognition frequency and the peak optical density of the band were compared between groups by chi(2) and t-tests. OA sera recognized various bands for the chondrocytes, and one of these (47-kDa) was specific for the OA sera. In two OA patients whose treatment outcome was less favorable, the,reactivity against the 47-kDa protein was relatively high. In addition, the OA sera clearly cross-reacted with recombinant HSP47. Based on these findings, an autoimmune reaction against chondrocytes could be one of the exaggerating and/or perpetuating mechanisms in the pathophysiology of osteoarthritic TMJs, and the humoral antibody titre against the HSP47-like protein derived from the chondrocytes could be one of the possible markers for the prognosis of the joint pathology. (C) 1999 Elsevier Science Ltd. All rights reserved.

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  • Cyclic mechanical stress induces extracellular matrix degradation in cultured chondrocytes via gene expression of matrix metalloproteinases and interleukin-1 Reviewed

    T Fujisawa, T Hattori, K Takahashi, T Kuboki, A Yamashita, M Takigawa

    JOURNAL OF BIOCHEMISTRY   125 ( 5 )   966 - 975   1999.5

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    To clarify the mechanism of cartilage degradation induced by mechanical stress, we investigated the influence of cyclic tension force (CTF) on the metabolism of cultured chondrocytes. The chondrocytes were exposed to CTF using a Flexercell strain unit. Five or 15 kPa of high frequency CTF significantly inhibited the syntheses of DNA, proteoglycan, collagen, and protein, Fifteen kPa of high frequency CTF induced the expression of interleukin-1 (IL-1), matrix metalloproteinase (MMP)-2 and -9 mRNA, and increased the production of pro- and active-MMP-9. The degradation of proteoglycan was inhibited by and MMP inhibitor, indicating that MMPs are involved in the degradation of proteoglycans induced by high frequency CTF, Moreover, reducing the frequency of CTF from high to low decreased the inhibition of proteoglycan synthesis, These findings suggest that the CTF frequency is one of the key determinants of chondrocyte metabolism. Low magnitude CTF, whether high or low frequency, did not cause the gene expression of cartilage degradation factors, suggesting that this CTF magnitude causes only minor changes in the cartilage matrix, High magnitude and frequency CTF caused the gene expression of IL-1 and MMP-9, followed by increases in the production of MMP-2 and -9 proteins, suggesting that excessive and continuous cyclic mechanical stress induces the production of IL-1 and MMP-9, resulting in cartilage degradation.

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  • Involvement of cis-acting repressive element(s) in the 3'-untranslated region of human connective tissue growth factor gene. Reviewed

    Kubota, S, Hattori, T, Nakanishi, T, Takigawa, M

    FEBS Letters   450   84 - 88   1999

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  • Demonstration of receptors specific for connective tissue growth factor on a human chondrocytic cell line (HCS-2/8)

    T Nishida, T Nakanishi, T Shimo, M Asano, T Hattori, T Tamatani, K Tezuka, M Takigawa

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   247 ( 3 )   905 - 909   1998.6

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    The presence of receptors specific for connective tissue growth factor (CTGF) was demonstrated on a human chondrosarcoma-derived chondrocytic cell Line, HCS-2/8. The binding of I-125-labeIed recombinant CTGF to HCS-2/8 cells was inhibited by unlabeled CTGF but not by PDGF-BB or bFGF. Scatchard analysis revealed the presence of two classes of binding sites with Rd values of 18.6 and 259 nM on cells. A cross-linking study revealed the formation of I-12S-CTGF-receptor complex with an apparent molecular weight of 280 kDa, The I-125-CTGF-receptor complex disappeared almost completely on the addition of unlabeled CTGF but not PDGF-BB or bFGF, In addition, the I-125-CTGF-receptor complex was immunoprecipitated with anti-CTGF antiserum but not with anti-PDGF receptor antiserum. These findings suggest that CTGF directly binds to specific receptor molecules on HCS-2/8 cells. (C) 1998 Academic Press.

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  • Nitric oxide mediates interleukin-1-induced gene expression of matrix metalloproteinases and basic fibroblast growth factor in cultured rabbit articular chondrocytes Reviewed

    K Sasaki, T Hattori, T Fujisawa, K Takahashi, H Inoue, M Takigawa

    JOURNAL OF BIOCHEMISTRY   123 ( 3 )   431 - 439   1998.3

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    We recently reported that nitric oxide (NO), which is produced by chondrocytes treated with interleukin-1 beta (IL-1), releases basic fibroblast growth factor (bFGF) stored in the matrix of articular chondrocytes, To clarify the mechanism of the IL-l-induced bFGF release, we investigated the production and gene expression of bFGF, matrix metalloproteinases (MMPs), syndecan 3, and inducible NO synthase (iNOS) by IL-l-treated rabbit articular chondrocytes. IL-1 stimulated not only the release of bFGF but also the production of it, Gelatin and casein zymography revealed that IL-1 stimulated the production of not only MMP-9 but also MMP-3, The increase in the production of these MMPs preceded the IL-1-stimulated bFGF release, An MMP inhibitor partially suppressed the release of bFGF, indicating that matrix degradation is at least partially involved in the IL-l-stimulated bFGF release even if increased production of bFGF is related to the release, IL-1 sequentially stimulated mRNA expression of iNOS, membrane type 1-MMP, MMP-9 and -3, and bFGF, in that order, N-G-Monomethyl-L-arginine, an inhibitor of NO production, inhibited gene expression of MMP-9 and bFGF. These findings suggest that elevation of the NO level via iNOS mRNA expression stimulated by IL-1 mediates gene expression and production of MMPs and bFGF, resulting in the release of bFGF, and also reveal molecular mechanisms implicating the degradation of articular cartilage followed by angiogenesis in the synovium in arthritic joints.

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  • Demonstration of receptors for epidermal growth factor on cultured rabbit chondrocytes and regulation of their expression by various growth and differentiation factors. Reviewed

    Nishida,T, Nakanishi,T, Shimo,T, Asano,M, Hattori,T, Tamatani,T, Tezuka,K, Takigawa,M

    Biochem.Biophys.Res.Commun.   183   14 - 20   1998

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  • Isolation and characterization of a rheumatoid arthritis-specific antigen(RA-A47) from a human chondrocytic cell line(HCS-2/8) Reviewed

    Takako Hattori, Takuo Fujisawa, Kazuhiro Sasaki, Yasutaka Yutani, Tohru Nakanishi, Kojiro Takahashi, Masaharu Takigawa

    Biochem. Biophys. Res. Commun.   245 ( 3 )   679 - 683   1998

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    Two types of 47 kDa antigen specifically recognized by sera from rheumatoid arthritis (RA) patients were isolated from the membrane fraction of a human chondrosarcoma-derived chondrocytic cell line (HCS-2/8) by a 2-step procedure: preparative SDS-PAGE and reverse-phase HPLC. An N-terminal amino acid sequence in one of the 47 kDa antigens, named RA-A47, had 81% homology to that deduced from the DNA sequence of the colligin gene which is reported as human hsp47 gene, and 100% homology to that deduced from the DNA sequence of colligin-2 gene, a homologue of colligin. The RA-A47 cross-reacted with a monoclonal antibody raised against chick heat shock protein (Hsp) 47 and bound to gelatin. The expression of the ra-a47 gene was enhanced by heat shock treatment and TGF-β stimulation. These findings suggest that RA-A47 is a Hsp47-like protein, presumably the product of the colligin-2 gene, and that a collagen-specific molecular chaperone(s) such as Hsp47 and/or RA-A47 is involved in cartilage destruction in RA.

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  • Specific serum antibodies against membranous proteins of a human immortal chondrocytic cell line (HCS-2/8) in rheumatoid arthritis and their relationship to the natural history of this disease Reviewed

    Akira Sakawa, Yasutaka Yutani, Kentaro Inui, Akira Shimazu, Yoshiki Yamano, Akira Kinosita, Fujio Suzuki, Takako Hattori, Masaharu Takigawa

    Journal of Bone and Mineral Metabolism   14 ( 3 )   146 - 152   1996.9

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    An immortal human chondrocytic cell line (HCS-2/8) derived from a chondrosarcoma was used as a source of human antigens to find humoral antibodies to cell surface proteins of human chondrocytes in sera from patients with rheumatoid arthritis (RA). Membrane fractions prepared from the cell line were subjected to Western blot analysis using RA and normal sera as probes. RA sera recognized about a dozen bands, but three of these bands, with molecular weights of 105 kDa, 68 kDa, and 47 kDa, were found to be specific for the RA sera (P < 0.05). These bands disappeared following V8 protease digestion, indicating that they were proteins. Among patients with 4 years or more of RA disease activity, reactivity against 105-kDa and 68-kDa proteins was relatively high in those whose joints showed a high degree of erosion. We suspect that levels of these two antibodies are suggestive of changes associated with the natural course of RA.

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  • Novel FNR homologues identified in four representative oral facultative anaerobes: Capnocytophaga ochracea, Capnocytophaga sputigena, Haemophilus aphrophilus, and Actinobacillus actinomycetemcomitans Reviewed

    T Hattori, K Takahashi, T Nakanishi, H Ohta, K Fukui, S Taniguchi, M Takigawa

    FEMS MICROBIOLOGY LETTERS   137 ( 2-3 )   213 - 220   1996.4

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    Based upon DNA sequence data and positive immunochemical reactivity of expressed protein, novel homologues of the FNR family were identified in four representative oral facultative anaerobes: Capnocytophaga ochracea, Capnocytophaga sputigena, Haemophilus aphrophilus, and Actinobacillus actinomycetemcomitans. The similarity to E. coli FNR and to HlyX (itself 71% similar to E. coli FNR, while regulating expression of hemolysin operon in Actinobacillus pleuropneumoniae) was estimated from the deduced partial amino acid sequence to be, in the above order of tested species, 98, 98, 86, and 85%, and 75, 75, 88, and 88%, respectively. The phylogenetic relatedness indicates a rather closer link of HlyX to the FNR homologues from both pathogens, H. aphrophilus and A. actinomycetemcomitans. The possibility that the A. actinomycetemcomitans FNR homologue functions as a redox-sensing transcriptional factor to regulate, in addition to anaerobic respiration, microaerobic expression of the leukotoxin operon (Itx gene) is suggested.

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  • Nitric oxide mediates interleukin-1-induced matrix degradation and basic fibroblast groth factor release in cultured rabbit articular chondrocytes: A possible mechanism of pathological neovascularization in arthritis. Reviewed

    Tamura, T, Nakanishi, T, Kimura, Y, Hattori, T, Sasaki, K, Norimatsu, H, Takahashi, K, Takigawa, M

    Endocrinology   137 ( 9 )   3729 - 3737   1996

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  • Nitric oxide mediates interleukin-1-induced matrix degradation and basic fibroblast growth factor release in cultured rabbit articular chondrocytes: A possible mechanism of pathological neovascularization in arthritis

    Tomoo Tamura, Tohru Nakanishi, Yusuke Kimura, Takako Hattori, Kazuhiro Sasaki, Hiromichi Norimatsu, Kojiro Takahashi, Masaharu Takigawa

    Endocrinology   137 ( 9 )   3729 - 3737   1996

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    Prolonged incubation with interleukin-1β (IL-1) induced the release of large amounts of NO and subsequently inhibited DNA synthesis and the biosynthesis and accumulation of proteoglycans in cultured rabbit articular chondrocytes (RAC). IL-1 also inhibited DNA synthesis in bovine aortic endothelial cells (BAE). On the other hand, DNA synthesis in BAE cocultured with RAC was not inhibited by prolonged incubation with IL-1. Moreover, conditioned media from RAC incubated for a long period with IL-1 stimulated DNA synthesis in BAE alone. This growth stimulatory activity was mainly due to the release of basic fibroblast growth factor, a heparin-binding growth factor, into RAC culture. Gelatin zymography of the RAC culture medium revealed that IL-1 increased the production of matrix met alloproteinase-2 (MMP-2) and MMP-9. N(G)-Monomethyl-L-arginine, an inhibitor of NO synthesis, inhibited all of these actions of IL-1. These results indicate that NO from RAC treated with IL-1 stimulates MMPs, which, in turn, degrade the extracellular matrix produced by RAC, resulting in the release of large amounts of basic fibroblast growth factor stored in the matrix, which then stimulates adjacent BAE proliferation. Thus, NO produced from RAC treated with IL-1 may modulate angiogenesis in the synovium of arthritic patients.

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  • Expression of nerve growth factor family neurotrophins in a mouse osteoblastic cell line

    Tohru Nakanishi, Kojiro Takahashi, Chiharu Aoki, Kiyoshi Nishikawa, Takako Hattori, Shigehiko Taniguchi

    Biochemical and Biophysical Research Communications   198 ( 3 )   891 - 897   1994.2

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    With cultured osteoblastic cells, clone MC3T3-E1 derived from newborn mouse calvaria, the mRNAs encoding three representative neurotrophins, namely, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), were proved in estimation by the polymerase chain reaction (PCR) method. The increase and then subsequent decrease of all three mRNAs within the proliferation phase were followed by their gradual increase in the differentiation phase, with a tendency of enhancement by exogenous TGF-β as was particularly evident in the case of NGF. These findings were further substantiated by identification of NGF-like neurotrophins in the conditioned medium of the osteoblastic cells by an immunoblotting and neurite extension assay. © 1994 Academic Press, Inc.

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  • REPRESSION OF IN-VITRO TRANSCRIPTION OF THE ESCHERICHIA-COLI FNR AND NARX GENES BY FNR PROTEIN Reviewed

    K TAKAHASHI, T HATTORI, T NAKANISHI, T NOHNO, N FUJITA, A ISHIHAMA, S TANIGUCHI

    FEBS LETTERS   340 ( 1-2 )   59 - 64   1994.2

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    In facultative anaerobes, the anaerobic expression of respiratory genes is regulated by a transcriptional activator, FNR. Transcription in vitro of the E. coli fnr gene was repressed by its product, FNR. The transcription of the E. coli nar X gene encoding the nitrate sensor protein was likewise repressed. DNA truncation experiments for fnr and nar X genes indicated that multiple anaero-boxes in each promoter region are essential for repression by the FNR protein, but they also suggest that factor-independent upstream activation signals are operating with these promoters.

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  • Expression of nerve growth factor family neurotrophins in a mouse osteoblastic cell line. Reviewed

    Nakanishi, T, Takahashi, K, Aoki, C, Nishikawa, K, Hattori, T, Taniguchi, S

    Biochem. Biophys. Res. Commun.   198 ( 3 )   891 - 897   1994

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  • Differential expression of homeobox-containing genes Msx-1 and Msx-2 and homeoprotein Msx-2 expression during chick craniofacial development. Reviewed

    Nishikawa, K, Nakanishi, T, Aoki, C, Hattori, T, Takahashi, K, Taniguchi, S

    Biochem. Mol. Biol. Inter.   32 ( 4 )   763 - 771   1994

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  • Studies on phosphorylated transcriptional regulator(NarL)for DBE. coli nar(/)/DB operon by 31P-NMR spectroscopy.

    K. Takahashi, T. Hattori, H. Shindo, S. Noji, T. Nohno, S. Taniguchi

    Biochemistry and Molecular Biology International   31 ( 1 )   161 - 168   1993

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    The sequential transphosphorylation from autophosphorylated nitrate-sensing protein (NarX) to the transcriptional regulator protein (NarL), both operating in signal transduction to control the expression of the respiratory nitrate reductase (nar) operon in E. coli, was demonstrated with an in vitro reconstructed system to function similarly to other bacterial two-component regulatory systems. Over-expression system established by means of the pT7 promoter/polymerase provided both NarX and NarL proteins to reconstruct the in vitro transphosphorylation system. The phosphorylated NarL was detected, and the unstable phosphorylated group was directly assigned to acyl phosphate in the in vitro system by 31P-NMR spectroscopy.

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  • FNR-like protein as a regulator for the gene expression of anaerobic respiratory system in oral bacteria.

    Takahashi Kojiro, Hattori Takako, Ohta Hiroyuki, Noji Sumihare, Kato Keijiro, Taniguchi Shigehiko

    Japanese Journal of Oral Biology   34 ( 5 )   459 - 466   1992

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    TheE. coliFNR protein is known as a molecular oxygene sensor and a specific activator for the gene expression of anaerobic respiratory system. In order to survey metabolic response toward molecular oxygen in oral bacteria from viewpoint of FNR-like protein participation, the expression of FNR-like protein in five representative strains of oral bacteria (Actinobacillus actinomycetemcomitansand Streptococcus sanguis as facultative anaerobe, Wolinella recta as microaerophile, and Prevotella intermedia and Fusobacterium nucleatumas strict anaerobe) was investigated with the Western blot method using an anti-FNR rabbit serum prepared against the purifiedE. coliFNR. For only A. actinomycetemcomitansas a facultative anaerobe, the Western blot test was positive, whereas negative for other four strains. This implies the possibility that in A. actinomycetemcomitans, a regulatory mechanism similar to that in E. coli functions for the expression of anaerobic respiratory genes.<BR>The expression level of FNR-like protein in A. actinomycetemcomitans was found to be enhanced with decreasing rate of the fructose-limited growth at the redox potential fixed around-400 mV, andbe maximum at the redox potential around-250 mV with the growth rate fixed at 0.11 h-1 under the anaerobic conditions.

    DOI: 10.2330/joralbiosci1965.34.459

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Books

  • Molecular and Genetic Interactions between CCN2 and CCN3 behind Their Yin-Yang Collaboration.

    Kubota S, Kawata K, Hattori T, Nishida T( Role: Joint author)

    Int J Mol Sci., MDPI  2022 

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  • Cellular communication network factor 3 in cartilage development and maintenance.

    Kubota S, Kawaki H, Perbal B, Kawata K, Hattori T, Nishida T( Role: Joint author)

    J Cell Commun. Signal.  2021 

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  • Retrotransposons Manipulating Mammalian Skeletal Development in Chondrocytes

    Kubota S, Ishikawa T, Kawata K, Hattori T, Nishida T.( Role: Joint author)

    Int J Mol Sci., MDPI  2020.2 

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  • 低身長治療のみでなく関節機能維持によるアンチエイジング療法の開発を目的とした軟骨組織の概日リズム形成機構の解明

    ( Role: Sole author)

    一般社団法人至誠会  2019.4 

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    Language:Japanese

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  • New function of Tip60 in controlling triacylglycerol synthesis.

    ( Role: Sole author)

    Biotarget  2018.9 

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  • Generation and Analysis of Cartilage-Specific CCN2 Overexpression in Transgenic Mice.in Methods in Molecular Biology: CCN Proteins: Methods and Protocols

    Hattori T, Itoh S, and Takigawa M( Role: Joint author)

    Springer  2016 

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    Responsible for pages:391-403   Language:English

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  • Protocols for Screening for Binding Partners of CCN Proteins: Yeast Two-Hybrid System.in Methods in Molecular Biology: CCN Proteins: Methods and Protocols

    Hoshijima M, Hattori T, Takigawa M( Role: Joint author)

    Springer  2016 

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    Responsible for pages:145-154   Language:English

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  • Production of Recombinant CCN2 Protein in Escherichia coli.in Methods in Molecular Biology: CCN Proteins: Methods and Protocols

    Aoyama E, Hattori T, Kubota S and Takigawa M( Role: Joint author)

    Springer  2016 

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    Responsible for pages:77-84   Language:English

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  • Protein Imaging of CCN2 and CCN3 in Living Cells.in Methods in Molecular Biology: CCN Proteins: Methods and Protocols

    Hattori T, Hoshijima M, and Takigawa M( Role: Joint author)

    Springer  2016 

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    Responsible for pages:211-215   Language:English

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  • Cartilage-specific over-expression of CCN family member 2/connective tissue growth factor (CCN2/CTGF) stimulates insulin-like growth factor expression and bone growth

    ( Role: Sole author)

    2014.9 

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  • 骨伸長促進効果を有する結合組織成長因子CTGF/CCN2の低身長治療への応用のための基礎研究

    服部高子、西田崇、久保田聡( Role: Joint author)

    成長科学協会研究年報  2014.8 

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  • 骨軟骨血球系の統合形成におけるトランスモジュレーターとしてのCCN2の役割

    久保田, 聡, 滝川, 正春, 服部, 高子, 西田, 祟, 青山, 絵理子

    久保田聡  2007.3 

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  • Connective tissue growth factor (CTGF)/CCN2

    2007 

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  • Autoantigen and Molecular Chaperone in Rheumatoid Arthritis-Their roles in Metabolism of Chondrocytes

    ( Role: Contributor)

    2006 

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  • 1. 骨,6.石灰化の機構、骨と軟骨のバイオロジー

    服部高子, 滝川正春( Role: Contributor)

    金原出版  2002 

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  • 軟骨由来の慢性関節リウマチ関連抗原RA-A47に関する研究(Study on a rheumatoid arthritis-related antigen (RA-A47) isolated from chondrocytes).

    服部高子( Role: Sole author)

    2000.9 

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  • マトリクラインとMMP,現代医療

    服部高子, 滝川正春( Role: Contributor)

    現代医療社  2000 

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  • VEGF, 関節外科

    服部高子, 滝川正春( Role: Contributor)

    メジカルビュー社  1998 

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  • 血管新生に関与する因子とその作用機序-化学的因子,ボリアミン-

    血管新生療法-基礎と臨床,真興貿易 

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  • 石灰化の機構

    骨・軟骨の生物学-基礎知識 金原出版 

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MISC

  • 軟⾻組織においてCCN3の発現上昇は、年齢、荷重の有無に関わらず軟⾻ 変性度と相関する

    桑原 実穂, 廣瀬 一樹, 奥田 龍一郎, Janvier Habumugisha, 近藤 星, Shanqi Fu, 大野 充昭, 古松 毅之, 中田 英二, 滝川 正春, 久保田 聡, 服部 高子

    第46回日本分子生物学会年会   2023.12

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  • 軟骨組織の加齢とともに発現が上昇するCCN3は、その発現上昇と軟骨変性度が年齢、荷重の有無に関わらず相関する

    桑原 実穂, 廣瀬 一樹, 近藤 星, Fu Shanqi, 大野 充昭, 古松 毅之, 中田 英二, 滝川 正春, 久保田 聡, 服部 高子

    第96回日本生化学会大会   2023.11

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  • 軟骨組織におけるCCN3の老化マーカーとしての役割と、CCN3の異所性発現による加齢様退行性変化の促進

    桑原 実穂, 廣瀬 一樹, 近藤 星, 古松 毅之, 中田 英二, 原 哲也, 久保田 聡, 服部 高子

    日本結合組織学会学術大会プログラム・抄録集   55回   158 - 158   2023.6

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  • CCN3は軟骨細胞老化マーカーであり,年齢,荷重の有無に関わらず変形性関節症と相関する

    服部高子, 滝川正春, 久保田聡

    Journal of Oral Biosciences Supplement (Web)   2023   2023

  • 軟骨組織の加齢変性におけるCCN3の機能

    桑原実穂, 近藤 星, Fu Shanqi, 大野充昭, 古松毅之, 中田英二, 滝川正春, 服部高子, 久保田聡

    第95回日本生化学会   95回   1T14a - 08   2022.11

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  • Metformin regulates expression of long non-coding RNA, UCA1 and CCN2 in chondrocytes

    近藤星, 近藤星, 服部高子, 桑原実穂, FU Shanqi, 西田崇, 薬師寺翔太, 吉岡洋祐, 森谷徳文, 森谷徳文, 飯田征二, 滝川正春, 久保田聡

    日本分子生物学会年会プログラム・要旨集(Web)   45th   2022.11

  • DO NOT OVERWORK: CCN3 FOR LIFE IN CARTILAGE

    2022.10

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  • メトホルミンの軟骨細胞におけるlong non-coding RNA, UCA1およびCCN2の発現制御と代謝における意義

    2022.9

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  • CCN3の関節軟骨における発現は、年齢、荷重の有無に関わらず変形性関節症と相関する –股関節を用いた研究–

    2022.9

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  • 変形性股関節症とCCN3発現の相関

    廣瀬一樹, 服部高子, 桑原実穂, 滝川正春, 中田英二, 鉄永智紀, 山田和希, 佐藤嘉洋, 小浦 卓, 尾崎敏文, 久保田聡

    第40回日本骨代謝学会   40th   2022.7

  • The correlation between osteoarthritis of the hip and CCN3 expression

    廣瀬一樹, 中田英二, 服部高子, 鉄永智紀, 山田和希, 佐藤嘉洋, 桑原実穂, 滝川正春, 久保田聡, 尾崎敏文

    日本軟骨代謝学会プログラム・抄録集   34th ( 1 )   S152 - S152   2022

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  • グルタチオンによる破骨細胞形成促進にシステイニルロイコトリエン受容体CysLTR1は関与しない

    藤田洋史, 土生田宗憲, 服部高子, 久保田聡, 大内淑代

    日本酸化ストレス学会学術集会プログラム・抄録集   75th (CD-ROM)   2022

  • Induction of non-coding RNA and promotion of chondrocyte differentiation by metformin

    近藤星, 近藤星, 服部高子, 桑原実穂, FU Shanqi, 西田崇, 薬師寺翔太, 吉岡洋祐, 森谷徳文, 飯田征二, 滝川正春, 久保田聡

    日本軟骨代謝学会プログラム・抄録集   34th   2022

  • Cysltr1変異はリポポリサッカリドによるマウス頭蓋冠の骨破壊に影響しない

    藤田洋史, 土生田宗憲, 服部高子, 久保田聡, 大内淑代

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  • 変形性股関節症とCCN3発現の相関

    廣瀬一樹, 服部高子, 滝川正春, 中田英二, 鉄永智紀, 山田和希, 佐藤嘉洋, 小浦卓, 尾崎敏文, 久保田聡

    日本骨形態計測学会雑誌   32 ( 1 )   2022

  • 変形性股関節症とCCN3の相関

    廣瀬一樹, 廣瀬一樹, 中田英二, 鉄永智紀, 山田和希, 小浦卓, 井上智博, 服部高子, 滝川正春, 久保田聡, 尾崎敏文

    日本股関節学会学術集会プログラム・抄録集   49th   2022

  • 変形性股関節症とCCN3発現の相関

    廣瀬一樹, 廣瀬一樹, 中田英二, 鉄永智紀, 山田和希, 佐藤嘉洋, 小浦卓, 服部高子, 桑原実穂, 滝川正春, 久保田聡, 尾崎敏文

    日本整形外科学会雑誌   96 ( 8 )   2022

  • マウス副腎におけるUCP1の発現は寒冷刺激により上昇しない.

    藤田 洋史, 土生田 宗憲, 服部 高子, 久保田 聡, 公文 裕己, 大内 淑代

    第44回日本分子生物学会年会, 横浜(ハイブリッド開催)(口演)(P)[2P-0610]   2021.12

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  • Metformin promotes chondrocyte differentiation, which is accompanied by UCA1 induction.

    近藤星, 近藤星, 服部高子, 桑原実穂, FU Shanqi, 西田崇, 吉岡洋祐, 森谷徳文, 飯田征二, 滝川正春, 久保田聡

    日本分子生物学会年会プログラム・要旨集(Web)   44th   2021.12

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  • メトホルミンによるUCA1を介した軟骨保護作用の解析

    近藤 星, 服部高子, 桑原実穂, Fu Shanqi, 西田 崇, 薬師寺翔太, 吉岡洋祐, 森谷徳文, 飯田征二, 滝川正春, 久保田聡

    第42回岡山歯学会,岡山 (Web開催) (O)   40 ( 2 )   38 - 39   2021.11

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  • Cysltr1遺伝子変異は破骨細胞分化と炎症性骨破壊に影響しない

    藤田 洋史, 土生田 宗憲, 大野 充昭, 大橋 俊孝, 服部 高子, 久保田 聡, 大内 淑代

    第94回日本生化学会大会, 横浜(Web開催)[P-925]   94th   [P - 925]   2021.11

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  • メトホルミンのUCA1誘導および軟骨細胞分化促進作用

    近藤星, 服部高子, 桑原実穂, Fu Shanqi, 西田崇, 吉岡洋祐, 森谷徳文, 飯田征二, 滝川正春, 久保田聡

    第94回日本生化学会大会, 横浜(Web開催)(口演)(P)[P-715(1T13e-09)]   94th   [1T13e - 715)]   2021.11

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  • CCN3は関節軟骨の加齢性変性を促進する

    桑原 実穂, 近藤 星, Fu Shanqi, 大野 充昭, 古松 毅之, 中田 英二, 滝川 正春, 久保田 聡, 服部 高子

    日本骨代謝学会学術集会プログラム抄録集   39回   138 - 138   2021.10

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  • 変形性肩関節症モデルとしてのCCN3過剰発現マウス

    廣瀬 一樹, 服部 高子, 中田 英二, 鉄永 智紀, 山田 和希, 佐藤 嘉洋, 桑原 実穂, 尾崎 敏文, 滝川 正春, 久保田 聡

    日本骨代謝学会学術集会プログラム抄録集   39回   151 - 151   2021.10

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  • OCN3は関節軟骨の加齢性変性を促進する

    桑原 実穂, 近藤 星, Fu Shanqi, 大野 充昭, 古松 毅之, 中田 英二, 滝川 正春, 久保田 聡, 服部 高子

    日本骨代謝学会学術集会プログラム抄録集   39回   138 - 138   2021.10

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  • 変形性肩関節症モデルとしてのCCN3過剰発現マウス

    廣瀬 一樹, 服部 高子, 中田 英二, 鉄永 智紀, 山田 和希, 佐藤 嘉洋, 桑原 実穂, 尾崎 敏文, 滝川 正春, 久保田 聡

    日本骨代謝学会学術集会プログラム抄録集   39回   151 - 151   2021.10

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  • Circadian production of melatonin and its receptors influence metabolism and rhythmic gene expression in chondrocytes

    Shanqi Fu, 桑原実穂, 内田瑶子, 近藤星, 池亀美華, 丸山雄介, 服部淳彦, 林大智, 下村侑司, 高垣安紗美, 西田崇, 久保田聡, 服部高子

    第62回 日本生化学会 中国・四国支部例会 2021, 9, 10-11, 岡山 (WEB開催)   2021.9

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  • 成体神経筋接合部でのCCN ファミリーの役割

    大河原美静, 服部高子, 久保田聡, 伊藤美佳子, 増田章男, 滝川正春, Karen M. Lyons, 大野欽司

    第12回日本CCNファミリー研究会, 岡山(Web開催)   2021.9

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  • メトホルミンの軟骨細胞分化促進作用におけるUCA1とCCN2の役割

    近藤星, 服部高子, 桑原実穂, Fu Shanqi, 西田崇, 吉岡洋祐, 森谷徳文, 飯田征二, 滝川正春, 久保田聡

    第12回日本CCNファミリー研究会, 岡山(Web開催)(口演)   2021.9

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  • 変形性肩関節症とCCN3発現上昇との相関について

    廣瀬 一樹, 中田 英二, 服部 高子, 鉄永 智紀, 山田 和希, 佐藤 嘉洋, 桑原 実穂, 滝川 正春, 久保田 聡, 尾崎 敏文

    日本整形外科学会雑誌   95 ( 8 )   S1506 - S1506   2021.8

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  • 副腎髄質におけるUCP1タンパク質発現のUCP1レポーターマウスを用いた検証(UCP1-reporter mice reveal UCP1 protein expression in the adrenal medulla)

    Fujita Hirofumi, Habuta Munenori, Hattori Takako, Kubota Satoshi, Kumon Hiromi, Ohuchi Hideyo

    The Journal of Physiological Sciences   71 ( Suppl.1 )   105 - 105   2021.8

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  • non-coding RNAを介したメトホルミンの抗線維化作用の解析

    近藤 星, 服部 高子, 桑原 実穂, Fu Shanqi, 西田 崇, 吉岡 洋祐, 森谷 徳文, 飯田 征二, 滝川 正春, 久保田 聡

    日本口腔科学会雑誌   70 ( 2 )   134 - 134   2021.7

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  • 軟骨細胞老化促進因子としてのCCN3

    桑原実穂, 武内聡子, 近藤 星, Fu Shanqi, 大野充昭, 古松毅之, 中田英二, 滝川正春, 久保田聡, 服部高子

    第33回日本軟骨代謝学会、2021, 3, 26-7,岐阜(WEB開催) (O)   2021.3

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  • Plasma melatonin enhances growth, inhibits maturation, and adjusting circadian rhythm of melatonin production in chondrocytes

    Fu Shanqi, Kuwahara Miho, Uchida Yoko, Kondo Sei, Nishida Takashi, Ikegame Mika, Maruyama Yusuke, Hattori Atsuhiko, Takagaki Asami, Shimomura Yuji, Hayashi Daichi, Kubota Satoshi, Hattori Takako

    第33回日本軟骨代謝学会2021, 3, 26-7, 岐阜 (WEB開催)(O)   2021.3

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  • 腸内細菌の有無が胎児内軟骨成長に与える影響

    内田瑶子, 服部高子, 福原大樹, Fu Shanqi, 近藤 星, 桑原実穂, イスラム モニルル, 片岡広太, 江國大輔, 久保田聡, 森田 学

    第33回日本軟骨代謝学会、2021, 3, 26-7,岐阜 (WEB開催) (P)   2021.3

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  • 変形性肩関節症とCCN3発現上昇との相関について

    廣瀬一樹, 中田英二, 服部高子, 鉄永智紀, 山田和希, 佐藤嘉洋, 桑原実穂, 滝川正春, 久保田聡, 尾崎敏文

    移植(Web)   56 ( 4 )   2021

  • 軟骨組織におけるCCN3の老化促進作用

    桑原実穂, 桑原実穂, 近藤星, FU Shanqi, 大野充昭, 古松毅之, 中田英二, 皆木省吾, 滝川正春, 久保田聡, 服部高子

    日本分子生物学会年会プログラム・要旨集(Web)   43rd   2020.12

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  • メトホルミンの軟骨細胞分化に対する作用の解析

    近藤 星, 服部 高子, 桑原 実穂, Fu Shanqi, 森谷 徳文, 飯田 征二, 滝川 正春, 久保田 聡

    岡山歯学会雑誌   39 ( 2 )   36 - 36   2020.12

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  • non-coding RNAを介したメトホルミンの抗線維化作用の解析

    近藤星, 近藤星, 服部高子, 桑原実穂, FU Shanqi, 西田崇, 吉岡洋祐, 森谷徳文, 飯田征二, 滝川正春, 久保田聡

    日本分子生物学会年会プログラム・要旨集(Web)   43rd ( 2 )   134 - 134   2020.12

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  • ヒトの関節軟骨における周期的遺伝子発現に対するメラトニンの影響(Effect of melatonin on rhythmic gene expression in human articular cartilage)

    フシャンキ, 桑原 実穂, 内田 瑶子, 近藤 星, 西田 崇, 池亀 美華, 久保田 聡, 服部 高子

    日本骨代謝学会学術集会プログラム抄録集   38回   141 - 141   2020.10

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  • 発生と疾患にみる新たな細胞間コミュニケーション 母体腸内細菌叢の有無が胎児骨格形成に与える影響

    福原 瑶子, 服部 高子, 池亀 美華, 久保田 聡, 岡村 裕彦

    Journal of Oral Biosciences Supplement   2020   119 - 119   2020.9

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  • ヒト関節軟骨細胞における周期的遺伝子発現に対するメラトニンの影響(Effect of melatonin on rhythmic gene expression in human articular chondrocytes)

    Fu Shanqi, 桑原 実穂, 内田 瑶子, 林 大智, 下村 侑司, 高垣 安紗美, 西田 崇, 中田 英二, 古松 毅之, 近藤 星, 丸山 雄介, 服部 淳彦, 久保田 聡, 服部 高子

    日本生化学会大会プログラム・講演要旨集   93回   [2Z12 - 484)]   2020.9

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  • The impact of gut microbiome on embryonic endochondral ossification

    内田瑶子, 服部高子, 福原大樹, FU Shanqi, 近藤星, 桑原美穂, ISLAM Monirul, 片岡広太, 江國大輔, 久保田聡, 森田学

    日本軟骨代謝学会プログラム・抄録集   33rd   2020

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  • The investigation of the impact of mother gut microbiome of the endochondral ossification of embryo.

    福原瑶子, 服部高子, 池亀美華, 久保田聡, 岡村裕彦

    Journal of Oral Biosciences Supplement (Web)   2020   2020

  • CCN3 as a chondrocytic aging-accelerating factor

    桑原実穂, 武内聡子, 近藤星, FU Shanqi, 大野充昭, 古松毅之, 中田英二, 滝川正春, 久保田聡, 服部高子

    日本軟骨代謝学会プログラム・抄録集   33rd   2020

  • Cysltr1ノックアウトマウスを用いたシステイニルロイコトリエン受容体1の骨粗鬆症モデルにおける機能解明

    藤田洋史, 安藤碧, 大野充昭, 土生田宗憲, 服部高子, 久保田聡, 大内淑代

    日本解剖学会総会・全国学術集会講演プログラム・抄録集   125th   2020

  • 軟骨細胞は加齢にともなってCCN3を高発現し,その過剰発現は軟骨加齢を促進する

    桑原実穂, 武内聡子, 近藤星, FU Shanqi, 大野充昭, 古松毅之, 中田英二, 滝川正春, 久保田聡, 服部高子

    日本分子生物学会年会プログラム・要旨集(Web)   42nd   2019.12

  • CCNは軟骨細胞の加齢に伴い発現上昇し、過剰発現は軟骨加齢を促進する

    桑原 実穂, 武内 聡子, 近藤 星, Shanqi Fu, 大野 充昭, 古松 毅之, 中田 英二, 滝川 正春, 久保田 聡, 服部 高子

    岡山歯学会雑誌   38 ( 2 )   85 - 86   2019.12

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  • 長鎖(約6kb)lssODNおよびCRISPR/Cas9を用いたヒト科霊長類特異的lncRNAのマウス受精卵へのエレクトロポレーションによるノックインの試み

    近藤星, 桑原実穂, FU Shanqi, 武内聡子, 池田健司, 石川崇典, 大野充昭, 西田崇, 久保田聡, 服部高子

    日本生化学会大会(Web)   92nd   [2T12m - 06]   2019.9

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  • 長鎖(約6kb)IssODNおよびCRISPR/Cas9を用いたヒト科霊長類特異的lncRNAのマウス受精卵へのエレクトロポレーションによるノックインの試み

    近藤 星, 桑原 実穂, Fu Shanqi, 武内 聡子, 池田 健司, 石川 崇典, 大野 充昭, 西田 崇, 久保田 聡, 服部 高子

    日本生化学会大会プログラム・講演要旨集   92回   [2T12m - 06]   2019.9

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  • 軟骨細胞は松果体由来のメラトニン刺激で概日リズムを持ってメラトニンを産生し、増殖を促進し、肥大化を抑制する

    Fu Shanqi, 桑原 実穂, 内田 瑶子, 近藤 星, 西田 崇, 池亀 美華, 久保田 聡, 服部 高子

    日本骨代謝学会学術集会プログラム抄録集   37回   207 - 207   2019.9

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  • 破骨細胞におけるロイコトリエン系の機能解析:CRISPR-Cas9を用いたcysltr1ノックアウトマウスの作製

    藤田洋史, 土生田宗憲, 服部高子, 久保田聡, 大内淑代

    日本解剖学会総会・全国学術集会講演プログラム・抄録集   124th   2019

  • 長鎖(約6kb)ssODNおよびCRISPR/Cas9を用いたヒト科霊長類特異的lncRNAのマウス受精卵へのエレクトロポレーションによる高効率ノックインの試み

    近藤星, 桑原実穂, FU Shanqi, 池田健司, 石川崇典, 大野充昭, 西田崇, 久保田聡, 服部高子

    日本分子生物学会年会プログラム・要旨集(Web)   41st   2018.11

  • CCN2とRab14の相互作用が骨・軟骨細胞の基質産生に及ぼす役割

    星島 光博, 服部 高子, 田中 智代, 上岡 寛, 滝川 正春

    日本矯正歯科学会大会プログラム・抄録集   77回   239 - 239   2018.10

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  • CCN2とRab14の相互作用が骨・軟骨細胞の小胞輸送に及ぼす役割 軟骨分化促進因子CCN2の新たな細胞内機能

    星島 光博, 服部 高子, 青山 絵理子, 西田 崇, 久保田 聡, 上岡 寛, 滝川 正春

    Journal of Oral Biosciences Supplement   2018   448 - 448   2018.9

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  • 軟骨におけるメラトニンとその受容体の日周的合成は軟骨の律動的遺伝子発現に影響を及ぼす(Circadian production of melatonin and its receptors in cartilage influences chondrocyte rhythmic gene expression)

    Fu Shanqi, 桑原 実穂, 内田 瑶子, 林 大智, 下村 侑司, 高垣 安紗美, 西田 崇, 丸山 雄介, 池亀 美華, 服部 淳彦, 服部 高子, 久保田 聡

    日本生化学会大会プログラム・講演要旨集   91回   [1T14m - 250)]   2018.9

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  • 破骨細胞におけるロイコトリエン系の機能解明 CRISPR-Cas9を用いたalox5apノックアウトマウスの作製

    藤田 洋史, 長尾 僚祐, 土生田 宗憲, 服部 高子, 久保田 聡, 大内 淑代

    日本生化学会大会プログラム・講演要旨集   91st   [3P - 234]   2018.9

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  • ヒト科霊長類特異的lncRNAのエレクトロポレーションによる マウス受精卵への効率的なノックインの試み

    近藤 星, 桑原実穂, Fu Shanqi, 池田健司, 石川崇典, 大野充昭, 西田 崇, 久保田聡, 服部高子

    ブレインストーミング2018、瀬戸内市、2018, 9, 15 (P)   2018.9

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  • ゲノム編集マウスを用いた破骨細胞分化におけるロイコトリエン合成関連遺伝子の機能解析

    藤田洋史, 長尾僚祐, 土生田宗憲, 服部高子, 久保田聡, 大内淑代

    日本解剖学会総会・全国学術集会講演プログラム・抄録集   123rd   2018

  • CCN2とRab14の相互作用が骨・軟骨細胞の小胞輸送に及ぼす役割

    星島 光博, 服部 高子, 青山 絵理子, 西田 崇, 田中 智代, 久保田 聡, 上岡 寛, 滝川 正春

    生命科学系学会合同年次大会   2017年度   [2P - 0285]   2017.12

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  • 軟骨組織におけるメラトニン合成とその受容体発現は概日リズムを持ち、軟骨細胞の代謝に影響を及ぼす

    服部 高子, Fu Shanqi, 桑原 実穂, 内田 瑶子, 近藤 星, 林 大智, 下村 侑司, 高垣 安紗美, 西田 崇, 丸山 雄介, 池亀 美華, 服部 淳彦, 久保田 聡

    生命科学系学会合同年次大会   2017年度   [2P - 1190]   2017.12

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  • 軟骨細胞分化に関わる長鎖ノンコーディングRNAの骨形成における役割

    石川 崇典, 村瀬 友里香, 西田 崇, 服部 高子, 大野 充昭, 上岡 寛, 滝川 正春, 久保田 聡

    日本骨代謝学会学術集会プログラム抄録集   35回   166 - 166   2017.7

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  • Production of recombinant CCN2 protein in Escherichia coli International journal

    Eriko Aoyama, Takako Hattori, Satoshi Kubota, Masaharu Takigawa

    Methods in Molecular Biology   1489   77 - 84   2017

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    Recombinant proteins are important tools for understanding molecular functions in vitro. Recent progress in the generation of recombinant proteins is amazing. However, when we plan to produce them, we should choose the best method according to the nature and the use of the target recombinant protein. Degradation and mis-folding are major problems in producing active recombinant CCN2. The method shown in this chapter describes the appropriate conditions under which we can produce CCN2 and its truncated fragments in Escherichia coli.

    DOI: 10.1007/978-1-4939-6430-7_8

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  • Protocols for screening for binding partners of CCN proteins: Yeast two-hybrid system International journal

    Mitsuhiro Hoshijima, Takako Hattori, Masaharu Takigawa

    Methods in Molecular Biology   1489   145 - 154   2017

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    Yeast two-hybrid screening is a powerful method to identify proteins that interact with a protein of interest. CCN2 consists of four domains, and identification of new proteins that bind to individual domains of CCN2 may reveal a variety of CCN2 functions. To identify CCN2-interactive proteins that regulate CCN2 activity, we carried out GAL4-based yeast two-hybrid screening with a cDNA library derived from a chondrocytic cell line, HCS-2/8, with CCN2 cDNA used as a bait. In this chapter, we describe our methods for screening for CCN2 binding partners by this system in detail. This protocol may be applied to other CCN proteins as well.

    DOI: 10.1007/978-1-4939-6430-7_15

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  • Generation and analysis of cartilage-specific CCN2 overexpression in transgenic mice International journal

    Takako Hattori, Shinsuke Itoh, Masaharu Takigawa

    Methods in Molecular Biology   1489   391 - 403   2017

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    Recent progress in gene-editing technology has provided a strong impact for improved our understanding of molecular functions in living organisms. Here we describe our method to generate transgene-overexpressing mouse models, which method involves the use of tissue-specific promoters for analyzing a certain molecule (s) in special tissues. The protocol described in this chapter uses the Col2a1 promoter-enhancer, which is known for driving specific and strong transgene expression in cartilage and is based on several of our studies showing a positive role of the connective tissue growth factor (CCN2) in cartilage-bone development and maintenance of articular cartilage. These mice show strongly accelerated endochondral ossification resulting in enhanced bone elongation, as well as resistance to age-related articular degeneration. This protocol also describes how to analyze the molecular mechanisms of these phenomena by use of chondrocytes isolated from CCN2-overexpressing cartilage.

    DOI: 10.1007/978-1-4939-6430-7_32

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  • Protein imaging of CCN2 AND CCN3 in living cells International journal

    Takako Hattori, Mitsuhiro Hoshijima, Masaharu Takigawa

    Methods in Molecular Biology   1489   211 - 215   2017

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    Recent progress in molecular imaging technology has had a strong impact on improving our understanding of molecular translocation, receptor internalization, and interactions in living cells. The protocol in this chapter introduces an optimized technique for intracellular localization of CCN2 and CCN3 in live cells, one using GFP-tagged CCN2 and Halo-tagged CCN3.

    DOI: 10.1007/978-1-4939-6430-7_20

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  • 骨格形成における低密度リポたんぱく質受容体関連たんぱく質1(LRP1)の役割

    河田かずみ, 久保田聡, 久保田聡, 服部高子, 青山絵理子, 滝川正春, 滝川正春

    日本軟骨代謝学会プログラム・抄録集   30th   2017

  • 軟骨細胞分化に関わる長鎖ノンコーディングRNAの骨形成における役割

    石川崇典, 村瀬友里香, 村瀬友里香, 西田崇, 服部高子, 大野充昭, 上岡寛, 滝川正春, 滝川正春, 久保田聡, 久保田聡

    日本骨代謝学会学術集会プログラム抄録集   35th   2017

  • 軟骨組織におけるメラトニンの作用

    服部 高子, 西田 崇, 久保田 聡, Fu Shanqi, 林 大智, 下村 侑司, 高垣 安紗美

    Journal of Oral Biosciences Supplement   2016   225 - 225   2016.9

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  • Role of CCN2 in Amino Acid Metabolism of Chondrocytes

    Yurika Murase, Takako Hattori, Eriko Aoyama, Takashi Nishida, Aya Maeda-Uematsu, Harumi Kawaki, Karen M. Lyons, Akira Sasaki, Masaharu Takigawa, Satoshi Kubota

    JOURNAL OF CELLULAR BIOCHEMISTRY   117 ( 4 )   927 - 937   2016.4

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    CCN2/connective tissue growth factor (CTGF) is a multi-functional molecule that promotes harmonized development and regeneration of cartilage through its matricellular interaction with a variety of extracellular biomolecules. Thus, deficiency in CCN2 supply profoundly affects a variety of cellular activities including basic metabolism. A previous study showed that the expression of a number of ribosomal protein genes was markedly enhanced in Ccn2-null chondrocytes. Therefore, in this study, we analyzed the impact of CCN2 on amino acid and protein metabolism in chondrocytes. Comparative metabolome analysis of the amino acids in Ccn2-null and wild-type mouse chondrocytes revealed stable decreases in the cellular levels of all of the essential amino acids. Unexpectedly, uptake of such amino acids was rather enhanced in Ccn2-null chondrocytes, and the addition of exogenous CCN2 to human chondrocytic cells resulted in decreased amino acid uptake. However, as expected, amino acid consumption by protein synthesis was also accelerated in Ccn2-null chondrocytes. Furthermore, we newly found that expression of two genes encoding two glycolytic enzymes, as well as the previously reported Eno1 gene, was repressed in those cells. Considering the impaired glycolysis and retained mitochondrial membrane potential in Ccn2-null chondrocytes, these findings suggest that Ccn2 deficiency induces amino acid shortage in chondrocytes by accelerated amino acid consumption through protein synthesis and acquisition of aerobic energy. Interestingly, CCN2 was found to capture such free amino acids in vitro. Under physiological conditions, CCN2 may be regulating the levels of free amino acids in the extracellular matrix of cartilage. J. Cell. Biochem. 117: 927-937, 2016. (c) 2015 Wiley Periodicals, Inc.

    DOI: 10.1002/jcb.25377

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  • 骨格形成における低密度リポタンパク受容体関連タンパク1(LRP1)の役割

    KAWATA Kazumi, KUBOTA Satoshi, KUBOTA Satoshi, HATTORI Takako, AOYAMA Eriko, TAKIGAWA Masaharu, TAKIGAWA Masaharu

    日本骨代謝学会学術集会プログラム抄録集   34th   223 - 223   2016

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  • Involvement of multiple CCN family members in platelets that support regeneration of joint tissues

    Chikako Hara, Satoshi Kubota, Takashi Nishida, Miki Hiasa, Takako Hattori, Eriko Aoyama, Yoshinori Moriyama, Hiroshi Kamioka, Masaharu Takigawa

    MODERN RHEUMATOLOGY   26 ( 6 )   940 - 949   2016

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    Objectives: Platelet-rich plasma (PRP) has been widely used to enhance the regeneration of damaged joint tissues, such as osteoarthritic and rheumatoid arthritic cartilage. The aim of this study is to clarify the involvement of all of the CCN family proteins that are crucially associated with joint tissue regeneration.
    Methods: Cyr61-CTGF-NOV (CCN) family proteins in human platelets and megakaryocytic cells were comprehensively analyzed by Western blotting analysis. Production of CCN family proteins in megakaryocytes in vivo was confirmed by immunofluorescence analysis of mouse bone marrow cells. Effects of CCN family proteins found in platelets on chondrocytes were evaluated by using human chondrocytic HCS-2/8 cells.
    Results: Inclusion of CCN2, a mesenchymal tissue regenerator, was confirmed. Of note, CCN3, which counteracts CCN2, was newly found to be encapsulated in platelets. Interestingly, these two family members were not detectable in megakaryocytic cells, but their external origins were suggested. Furthermore, we found for the first time CCN5 and CCN1 that inhibits ADAMTS4 in both platelets and megakaryocytes. Finally, application of a CCN family cocktail mimicking platelets onto HCS-2/8 cells enhanced their chondrocytic phenotype.
    Conclusions: Multiple inclusion of CCN1, 2 and 3 in platelets was clarified, which supports the harmonized regenerative potential of PRP in joint therapeutics.

    DOI: 10.3109/14397595.2016.1155255

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  • Investigation on long non‐coding RNAs that are associated with chondrocytic phenotype

    ISHIKAWA Takanori, MURASE Yurika, MURASE Yurika, NISHIDA Takashi, HATTORI Takako, TAKIGAWA Masaharu, KAMIOKA Hiroshi, KUBOTA Satoshi, KUBOTA Satoshi

    日本RNA学会年会要旨集   18th   ROMBUNNO.254   2016

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  • 軟骨細胞形質を支える長鎖非コードRNA

    石川崇典, 石川崇典, 久保田聡, 久保田聡, 村瀬友里香, 西田崇, 服部高子, 滝川正春, 滝川正春

    日本軟骨代謝学会プログラム・抄録集   29th   2016

  • 血小板に含まれるCCNファミリータンパク質の解析と軟骨再生への応用

    原規子, 原規子, 久保田聡, 久保田聡, 青山絵理子, 服部高子, 滝川正春, 滝川正春

    日本軟骨代謝学会プログラム・抄録集   29th   2016

  • 軟骨組織におけるメラトニンの作用

    服部高子, 西田崇, 久保田聡

    Journal of Oral Biosciences Supplement (Web)   2016   2016

  • 軟骨細胞形質に関わる長鎖非コードRNAの探索

    石川崇典, 石川崇典, 村瀬友里香, 西田崇, 服部高子, 滝川正春, 滝川正春, 上岡寛, 久保田聡, 久保田聡

    日本骨代謝学会学術集会プログラム抄録集   34th   222 - 222   2016

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  • CCN2とRab14の相互作用が軟骨細胞の小胞輸送に及ぼす役割

    星島光博, 星島光博, 服部高子, 滝川正春, 上岡寛

    日本矯正歯科学会大会プログラム・抄録集   75th   2016

  • 成熟破骨細胞のアクチンリング形成におけるCD302の機能とCCN2による制御

    青山 絵理子, 星島 光博, 服部 高子, 久保田 聡, 滝川 正春

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   88回・38回   [3T23 - 09(3P0069)]   2015.12

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  • 骨細胞の作用を介した破骨細胞形成におけるCCN2の役割

    西田 崇, 久保田 聡, 服部 高子, Bonewald Lynda F., 滝川 正春

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   88回・38回   [2P0151] - [2P0151]   2015.12

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  • CCN2は骨細胞を介して破骨細胞形成を制御する

    西田 崇, 久保田 聡, 服部 高子, 滝川 正春, Bonewald L.F.

    Journal of Oral Biosciences Supplement   2015   231 - 231   2015.9

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  • 破骨細胞分化における新規アクチン骨格制御因子としてのDCL-1/CD302の役割とCCN2との関連

    青山 絵理子, 星島 光博, 服部 高子, 久保田 聡, 滝川 正春

    Journal of Oral Biosciences Supplement   2015   230 - 230   2015.9

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  • Cross Sectional Patient‐Reported Survey on Asthma Control and Associated Burdens in Japanese Patients with Asthma in 2013

    IWANAGA Takashi, KUMAR Maya, GOREN Amir, MUKAI Isao, HATTORI Takako

    Therapeutic Research   36 ( 3 )   235 - 246   2015.3

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  • 破骨細胞分化における新規アクチン骨格制御因子としてのDCL-1/CD302の役割とCCN2との関連

    青山絵理子, 星島光博, 服部高子, 久保田聡, 久保田聡, 滝川正春

    Journal of Oral Biosciences Supplement (Web)   2015   2015

  • 新たな破骨細胞制御因子DCL-1/CD302の作用機構の解明とCCN2との関連

    青山絵理子, 服部高子, 星島光博, 星島光博, 久保田聡, 久保田聡, 滝川正春

    日本骨代謝学会学術集会プログラム抄録集   33rd   194 - 194   2015

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  • 骨軟骨再生因子CCN2の軟骨細胞アミノ酸代謝への影響

    村瀬友里香, 村瀬友里香, 服部高子, 青山絵理子, 前田彩, 川木晴美, 佐々木朗, 滝川正春, 久保田聡

    日本軟骨代謝学会プログラム・抄録集   28th   2015

  • CCN2による軟骨細胞のアミノ酸代謝制御

    村瀬友里香, 村瀬友里香, 服部高子, 青山絵理子, 西田崇, 前田彩, 川木晴美, 佐々木朗, 滝川正春, 久保田聡

    日本骨代謝学会学術集会プログラム抄録集   33rd   217 - 217   2015

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  • CCN2は骨細胞を介して破骨細胞形成を制御する

    西田崇, 久保田聡, 久保田聡, 服部高子, 滝川正春

    Journal of Oral Biosciences Supplement (Web)   2015   2015

  • 骨伸長促進効果を有する結合組織成長因子CTGF/CCN2の低身長治療への応用のための基礎研究

    服部高子, 西田崇, 久保田聡

    成長科学協会研究年報   ( 38 )   129 - 133   2015

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    結合組織成長因子(CTGF/CCN2)を低身長治療に応用するための基礎研究として、効率良く、安全に軟骨組織でCTGF/CCN2を誘導し、骨成長を促進する方法の確立を目指した。軟骨組織特異的CCN2過剰発現マウスの培養肋軟骨細胞よりRNAの単離とマイクロアレイ遺伝子解析を行った結果、多くの遺伝子発現の増減が観察された。パスウェイ解析では内軟骨性骨形成への関与が示唆されている遺伝子の増減やIGF-I、IIの発現上昇、多くのlnc RNAの発現抑制が検出され、現在も検索、追試験を行っている。また、培養肋軟骨細胞のシグナル伝達経路を解析し、チロシンキナーゼ型受容体のリン酸化誘導を確認した結果、リン酸化が確認されたチロシンキナーゼ群は、これまで内軟骨性骨形成で活性化が確認されているものがほとんどであった。

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  • 軟骨特異的CCN3過剰発現は内軟骨性骨化の遅延と関節変性を誘発する

    服部高子, 角谷宏一, 桑原実穂, 大野充昭, 星島光博, 星島光博, 窪木拓男, 久保田聡, 久保田聡, 滝川正春, 滝川正春

    日本骨代謝学会学術集会プログラム抄録集   33rd   158 - 158   2015

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  • CCN2とRab14の相互作用が軟骨細胞の小胞輸送に及ぼす役割

    星島光博, 星島光博, 服部高子, 青山絵理子, 西田崇, 上岡寛, 滝川正春

    日本軟骨代謝学会プログラム・抄録集   28th   232 - 232   2015

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  • 新たなCCN2結合因子DCL-1の破骨細胞分化における役割

    青山 絵理子, 星島 光博, 服部 高子, 久保田 聡, 滝川 正春

    Journal of Oral Biosciences Supplement   2014   105 - 105   2014.9

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  • 新たなCCN2結合因子DCL-1の破骨細胞分化における役割

    青山絵理子, 星島光博, 服部高子, 久保田聡, 滝川正春, 滝川正春

    Journal of Oral Biosciences Supplement (Web)   2014   2014

  • SOX9のユビキチンリガーゼE6-AP/UBE3Aは正常な骨格形成に必須である

    服部高子, 木住野達也, SHELLEY Stephen, HEIDI Eberspaecher, 巻さゆみ, 滝川正春, 西田崇, 久保田聡, DE CROMBRUGGHE Benoit, 安田秀世, 安田秀世

    日本分子生物学会年会プログラム・要旨集(Web)   37th   2014

  • 軟骨分化促進因子CCN2の新たな細胞内機能:CCN2とRab14GTPaseの相互作用が軟骨細胞の小胞輸送に及ぼす役割

    星島光博, 星島光博, 服部高子, 青山絵理子, 西田崇, 上岡寛, 滝川正春

    日本骨代謝学会学術集会プログラム抄録集   32nd   302 - 302   2014

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  • CCN2結合因子DCL-1の破骨細胞分化制御因子としての役割

    青山絵理子, 服部高子, 滝川正春, 滝川正春

    日本骨代謝学会学術集会プログラム抄録集   32nd   203 - 203   2014

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  • E6-AP/UBE3AはSOX9のユビキチンリガーゼである

    服部高子, 木住野達也, STEPHEN Shelley, EBERSPAECHER Heidi, 巻さゆみ, 滝川正春, DE CROMBRUGGHE Benoit, 安田秀世, 安田秀世, 安田秀世

    日本軟骨代謝学会プログラム・抄録集   27th   2014

  • 軟骨細胞にてエネルギー産生を支えるCCN2の新たな役割

    前田彩, 前田彩, 久保田聡, 久保田聡, 川木晴美, 河田かずみ, 三宅由晃, 服部高子, 西田崇, 森谷徳文, LYONS Karen M, 飯田征二, 滝川正春, 滝川正春

    日本軟骨代謝学会プログラム・抄録集   27th   2014

  • E6-AP/UBE3AはSOX9のユビキチンリガーゼとして軟骨組織の分化を制御する

    服部高子, 木住野達也, STEPHEN Shelley, EBERSPAECHER Heidi, 巻さゆみ, 滝川正春, DE CROMBRUGGHE Benoit, 安田秀世, 安田秀世

    日本生化学会大会(Web)   87th   [4T10p - 11]   2014

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  • 軟骨特異的CCN3過剰発現は軟骨の最終分化の遅延だけでなく,変形性関節症を誘発する

    服部高子, 大野充昭, 星島光博, 星島光博, 角谷宏一, 窪木拓男, 滝川正春

    Journal of Oral Biosciences Supplement (Web)   2014   2014

  • 破骨細胞分化における新規CCN2結合タンパク質DCL-1の発現と機能

    青山絵理子, 星島光博, 服部高子, 久保田聡, 滝川正春

    日本生化学会大会(Web)   87th   [2T14p - 14]   2014

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  • CCNファミリー遺伝子の発現プロフィールの操作を介したCCN3の線維化抑制作用の理解(Understanding the anti-fibrotic role of CCN3 through manipulation of CCN family gene expression profile)

    El Kader Tarek Abd, Kubota Satoshi, Janune Danilo, Nishida Takashi, Hattori Takako, Aoyama Eriko, Perbal Bernard, Kuboki Takuo, Takigawa Masaharu

    日本生化学会大会プログラム・講演要旨集   86回   1T11a - 15   2013.9

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  • 軟骨細胞の代謝の基本を支えるCCN2の重要性(Essential role of CCN2 that supports the basal energy metabolism in chondrocytes)

    前田 彩, 久保田 聡, 三宅 由晃, 河田 かずみ, 服部 高子, 西田 崇, 森谷 徳文, 川木 晴美, カレン・ライアン, 飯田 征二, 滝川 正春

    日本生化学会大会プログラム・講演要旨集   86回   2T06a - 15   2013.9

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  • CCNファミリー研究のメルティングポット CCN2は軟骨細胞のエネルギー代謝に重要である

    前田 彩, 久保田 聡, 川木 晴美, 河田 かずみ, 三宅 由晃, 服部 高子, 西田 崇, 森谷 徳文, 飯田 征二, 滝川 正春

    Journal of Oral Biosciences Supplement   2013   95 - 95   2013.9

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  • CCN2は軟骨細胞のエネルギー代謝に重要である

    前田彩, 前田彩, 久保田聡, 川木晴美, 河田かずみ, 三宅由晃, 服部高子, 西田崇, 森谷徳文, 飯田征二, 滝川正春

    Journal of Oral Biosciences Supplement (Web)   2013   ROMBUNNO.SS9‐5 (WEB ONLY)   2013

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  • 軟骨特異的CCN3過剰発現による内軟骨性骨形成の修飾

    服部高子, 大野充昭, 星島光博, 角谷宏一, 桑原実穂, 三宅佳子, 窪木拓男, 滝川正春

    Journal of Oral Biosciences Supplement (Web)   2013   2013

  • CCN3の軟骨特異的過剰発現は内軟骨性骨形成の遅延を誘発する

    角谷宏一, 服部高子, 桑原実穂, 大野充昭, 星島光博, 窪木拓男, 滝川正春

    Journal of Oral Biosciences Supplement (Web)   2013   2013

  • Rab14GTPaseのCCN2/CTGF結合因子としての同定,およびこれらの相互作用が軟骨細胞の小胞輸送に及ぼす役割

    星島光博, 星島光博, 服部高子, 青山絵理子, 西田崇, 滝川正春, 滝川正春

    Journal of Oral Biosciences Supplement (Web)   2013   2013

  • Rab14GTPaseのCCN2/CTGF結合因子としての同定と,これらの相互作用が軟骨細胞の小胞輸送に及ぼす役割

    星島光博, 星島光博, 服部高子, 青山絵理子, 西田崇, 山城隆, 滝川正春, 滝川正春

    日本軟骨代謝学会プログラム・抄録集   26th   202 - 202   2013

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  • CCN2とRab14GTPaseの相互作用が軟骨細胞の小胞輸送に及ぼす役割

    星島光博, 星島光博, 服部高子, 青山絵理子, 西田崇, 滝川正春, 滝川正春

    日本分子生物学会年会プログラム・要旨集(Web)   36th   448 - 448   2013

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  • 軟骨特異的CCN3過剰発現は内軟骨性骨形成の不全より骨異形性を誘発する

    服部高子, 大野充昭, 星島光博, 角谷宏一, 桑原実穂, 三宅佳子, 窪木拓男, 滝川正春

    日本分子生物学会年会プログラム・要旨集(Web)   36th   2013

  • CCN3の抗線維化効果に伴うCCNファミリー遺伝子発現プロファイルの変化

    タレック アブドエルケーダー, タレック アブドエルケーダー, 久保田聡, 久保田聡, ダニーロ ジャヌネ, 西田崇, 服部高子, 青山絵理子, 窪木拓男, 滝川正春

    岡山歯学会雑誌   32 ( 2 )   83 - 83   2013

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  • CCN2/CTGFとRab14 GTPaseの相互作用が軟骨細胞の小胞輸送に及ぼす役割

    星島光博, 星島光博, 服部高子, 青山絵理子, 西田崇, 滝川正春

    岡山歯学会雑誌   32 ( 2 )   85 - 86   2013

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  • CCN2/CTGFとRab14 GTPaseの相互作用が軟骨細胞の小胞輸送に及ぼす役割

    星島光博, 服部高子, 山城隆, 滝川正春

    日本矯正歯科学会大会プログラム・抄録集   72nd ( 2 )   2013

  • 軟骨細胞のエネルギー代謝を支えるCCN2/CTGF

    前田彩, 前田彩, 久保田聡, 三宅由晃, 河田かずみ, 西田崇, 服部高子, 森谷徳文, 川木晴美, LYONS Karen M., 飯田征二, 滝川正春

    日本軟骨代謝学会プログラム・抄録集   26th   2013

  • 軟骨特異的CCN3過剰発現は内軟骨性骨形成の遅延による骨梁形成の低下を誘発する

    服部高子, 大野充昭, 星島光博, 角谷宏一, 桑原実穂, 大家遥, 三宅佳子, 窪木拓男, 滝川正春

    日本軟骨代謝学会プログラム・抄録集   26th   2013

  • CCN2を構成する各モジュールの軟骨再生効果

    ABD EL KADER Tarek, ABD EL KADER Tarek, 久保田聡, 西田崇, 服部高子, 青山絵理子, JANUNE Danilo, 窪木拓男, 滝川正春, 滝川正春

    日本軟骨代謝学会プログラム・抄録集   26th   2013

  • CCN3の抗線維化効果に伴うCCNファミリー遺伝子発現プロファイルの変化

    DANILO Janune, ABD EL KADER Tarek, ABD EL KADER Tarek, 久保田聡, 西田崇, 服部高子, 青山絵里子, 窪木拓男, 滝川正春, 滝川正春

    Journal of Oral Biosciences Supplement (Web)   2013   2013

  • CCN2非依存性モジュールの軟骨再生能力(Cartilage regeneration potential of CCN2 independent modules)

    El Kader Tarek Abd, Kubota Satoshi, Nishida Takashi, Hattori Takako, Aoyama Eriko, Janune Danilo, Kuboki Takuo, Takigawa Masaharu

    日本再生歯科医学会誌   10 ( 1 )   50 - 50   2012.12

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  • 軟骨組織特異的低密度リポタンパク受容体欠損マウスにおける骨格形成(Deficiency of the low-density lipoprotein receptor related protein 1 (LRP1) in the cartilaginous tissue leads to skeletal dysmorphisms)

    河田 かずみ, 久保田 聡, 服部 高子, 青山 絵理子, ダニーロ・ジャヌネ, 滝川 正春

    日本生化学会大会プログラム・講演要旨集   85回   3P - 668   2012.12

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  • CCN2/CTGF欠損が軟骨細胞のエネルギー代謝に及ぼす影響

    前田 彩, 久保田 聡, 服部 高子, 西田 崇, 飯田 征二, 滝川 正春

    Journal of Oral Biosciences Supplement   2012   96 - 96   2012.9

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  • 軟骨細胞と骨芽細胞に対するCCN2独立モジュールの影響(Effects of CCN2 independent modules on chondrocytic and osteoblastic cells)

    El Kader Tarek Abd, Kubota Satoshi, Nishida Takashi, Hattori Takako, Aoyama Eriko, Janune Danilo, Kuboki Takuo, Takigawa Masaharu

    日本骨代謝学会学術集会プログラム抄録集   30回   232 - 232   2012.7

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  • 肥大軟骨細胞におけるβ-カテニンの特異的欠失は成長板の海綿骨形成障害をもたらす(Specific Deletion of Beta-Catenin in Hyper-trophic Chondrocytes Impairs Formation of Trabecular Bone in the Growth Plate)

    von der Mark Klaus, Hattori Takako, Hartmann Christine, Ryabova Svitlana, Gebhard Sonja, Pausch Frederike, Schlund Britta

    Connective Tissue Research   53 ( 1 )   49 - 50   2012.2

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  • Roles of the heterotypic CCN2-CCN3 and homotypic CCN2-CCN2 interactions in matrix synthesis in chondrocytes.

    M. Hoshijima, T. Hattori, E. Aoyama, T. Nishida, T. Yamashiro, M. Takigawa

    MOLECULAR BIOLOGY OF THE CELL   23   2012

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  • Roles of CCN2 in energy metabolism in chondrocytes.

    A. Maeda, S. Kubota, Y. Miyake, K. Kawata, T. Nishida, T. Hattori, N. Moritani, H. Kawaki, K. M. Lyons, S. Iida, M. Takigawa

    MOLECULAR BIOLOGY OF THE CELL   23   2012

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  • CCN3/NOVの軟骨特異的過剰発現は軟骨分化の最終段階に影響を及ぼす事により骨形成不全をきたす

    服部高子, 大野充昭, 星島光博, 角谷宏一, 桑原実穂, 三宅佳子, 窪木拓男, 滝川正春

    日本生化学会大会(Web)   85th   3T02 - 08   2012

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  • CCN2/CTGF-CCN3/NOVおよびCCN2-CCN2のダイマー形成が軟骨細胞の分化機能に及ぼす役割

    星島光博, 星島光博, 服部高子, 青山絵理子, 西田崇, 山城隆, 滝川正春, 滝川正春

    日本軟骨代謝学会プログラム・抄録集   25th   2012

  • 軟骨細胞の代謝システムにおけるCCN2の役割

    前田彩, 前田彩, 久保田聡, 三宅由晃, 河田かずみ, 服部高子, 西田崇, 森谷徳文, 川木晴美, LYONS Karen M., 飯田征二, 滝川正春

    岡山歯学会雑誌   31 ( 2 )   93 - 94   2012

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  • 軟骨細胞のエネルギー代謝におけるCCN2/CTGFの役割

    前田彩, 前田彩, 久保田聡, 三宅由晃, 河田かずみ, 西田崇, 服部高子, 森谷徳文, 川木晴美, LYONS Karen M., 飯田征二, 滝川正春

    日本分子生物学会年会プログラム・要旨集(Web)   35th   2012

  • CCN2/CTGF欠損が軟骨細胞のエネルギー代謝に及ぼす影響

    前田彩, 前田彩, 久保田聡, 服部高子, 西田崇, 飯田征二, 滝川正春

    Journal of Oral Biosciences Supplement (Web)   2012   2012

  • 軟骨細胞に対する、CCN2モジュールの単独・結合下での影響に関する評価(Evaluation of independent and combinational effect of CCN2 modules on chondorocytic cells)

    El Kdaer Tarek Abd, Kubota Satoshi, Nishida Takashi, Hattori Takako, Aoyama Eriko, Janune Danilo, Kuboki Takuo, Takigawa Masaharu

    日本骨代謝学会学術集会プログラム抄録集   29回   248 - 248   2011.7

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  • CCN2/CTGF誘導因子であるハルミンは軟骨形成を促進し、TNF-α誘発炎症反応を抑制する(HARMINE, AN INDUCER OF CCN2/CTGF, PROMOTES CHONDROGENESIS AND SUPPRESSES TNF-α-INDUCED INFLAMMATORY RESPONSE)

    Hara Emilio S.i, Ono Mitsuaki, Kubota Satoshi, Sonoyama Wataru, Hattori Takako, Takigawa Masaharu, Kuboki Takuo

    日本骨代謝学会学術集会プログラム抄録集   29回   232 - 232   2011.7

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  • 肥大軟骨細胞におけるβ-カテニンのみの欠失が成長板における海綿骨形成異常を引き起こす(Specific Deletion of beta-Catenin in Hypertrophic Chondrocytes Impairs Formation of Trabecular Bone in the Growth Plate)

    von der Mark Klaus, Hattori Takako, Hartmann Christine, Ryabova Svitlana, Gebhard Sonja, Pausch Frederike, Schlund Britta

    日本結合組織学会学術大会・マトリックス研究会大会合同学術集会プログラム・抄録集   43回・58回   39 - 39   2011.5

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  • 結合組織成長因子CCN2/CTGFは頭部神経堤由来の軟骨細胞分化に必須である

    服部高子, 寺岡徳光, 寺岡徳光, GEBHARDT Matthias, GEBHARDT Matthias, 内田瑶子, 内田瑶子, 新村兆一郎, 新村兆一郎, 福原大樹, 福原大樹, 滝川正春

    日本分子生物学会年会プログラム・要旨集(Web)   34th   2011

  • マウス成長板におけるCa2+結合タンパクsorcinの局在について

    河井まりこ, 服部高子, 滝川正春, 山本敏男

    Journal of Oral Biosciences   53 ( Supplement )   162 - 162   2011

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  • CCN2/CTGFとCCN3/NOVのヘテロおよびホモダイマー形成が軟骨細胞の基質合成に及ぼす役割

    星島光博, 星島光博, 服部高子, 西田崇, 山城隆, 滝川正春

    Journal of Oral Biosciences   53 ( Supplement )   141 - 141   2011

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  • CCN2/CTGFとCCN3/NOVのヘテロダイマー,およびCCN2のホモダイマー形成が軟骨細胞の基質合成に及ぼす役割

    星島光博, 星島光博, 服部高子, 青山絵理子, 西田崇, 山城隆, 滝川正春

    日本骨代謝学会学術集会プログラム抄録集   29th   247 - 247   2011

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  • The dimerization domain of SOX9 is required for transcription activation of a chondrocyte-specific chromatin DNA template

    Francoise Coustry, Chun-do Oh, Takako Hattori, Sankar N. Maity, Benoit de Crombrugghe, Hideyo Yasuda

    NUCLEIC ACIDS RESEARCH   38 ( 18 )   6018 - 6028   2010.10

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    Mutations in SOX9, a gene essential for chondrocyte differentiation cause the human disease campomelic dysplasia (CD). To understand how SOX9 activates transcription, we characterized the DNA binding and cell-free transcription ability of wild-type SOX9 and a dimerization domain SOX9 mutant. Whereas formation of monomeric mutant SOX9-DNA complex increased linearly with increasing SOX9 concentrations, formation of a wild-type SOX9-DNA dimeric complex increased more slowly suggesting a more sigmoidal-type progression. Stability of SOX9-DNA complexes, however, was unaffected by the dimerization mutation. Both wild-type and mutant SOX9 activated transcription of a naked Col2a1 DNA template. However, after nucleosomal assembly, only wild-type and not the mutant was able to remodel chromatin and activate transcription of this template. Using a cell line, in which the Col2a1 vector was stably integrated, no differences were seen in the interactions of wild-type and mutant SOX9 with the chromatin of the Col2a1 vector using ChIP. However, the mutant was unable to activate transcription in agreement with in vitro results. We hypothesize that the SOX9 dimerization domain is necessary to remodel the Col2a1 chromatin in order to allow transcription to take place. These results further clarify the mechanism that accounts for CD in patients harboring SOX9 dimerization domain mutations.

    DOI: 10.1093/nar/gkq417

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  • SOX9 is a major negative regulator of cartilage vascularization, bone marrow formation and endochondral ossification

    Takako Hattori, Catharina Mueller, Sonja Gebhard, Eva Bauer, Friederike Pausch, Britta Schlund, Michael R. Boesl, Andreas Hess, Cordula Surmann-Schmitt, Helga von der Mark, Benoit de Crombrugghe, Klaus von der Mark

    DEVELOPMENT   137 ( 6 )   901 - 911   2010.3

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    SOX9 is a transcription factor of the SRY family that regulates sex determination, cartilage development and numerous other developmental events. In the foetal growth plate, Sox9 is highly expressed in chondrocytes of the proliferating and prehypertrophic zone but declines abruptly in the hypertrophic zone, suggesting that Sox9 downregulation in hypertrophic chondrocytes might be a necessary step to initiate cartilage-bone transition in the growth plate. In order to test this hypothesis, we generated transgenic mice misexpressing Sox9 in hypertrophic chondrocytes under the control of a BAC-Col10a1 promoter. The transgenic offspring showed an almost complete lack of bone marrow in newborns, owing to strongly retarded vascular invasion into hypertrophic cartilage and impaired cartilage resorption, resulting in delayed endochondral bone formation associated with reduced bone growth. In situ hybridization analysis revealed high levels of Sox9 misexpression in hypertrophic chondrocytes but deficiencies of Vegfa, Mmp13, RANKL and osteopontin expression in the non-resorbed hypertrophic cartilage, indicating that Sox9 misexpression in hypertrophic chondrocytes inhibits their terminal differentiation. Searching for the molecular mechanism of SOX9-induced inhibition of cartilage vascularization, we discovered that SOX9 is able to directly suppress Vegfa expression by binding to SRY sites in the Vegfa gene. Postnatally, bone marrow formation and cartilage resorption in transgenic offspring are resumed by massive invasion of capillaries through the cortical bone shaft, similar to secondary ossification. These findings imply that downregulation of Sox9 in the hypertrophic zone of the normal growth plate is essential for allowing vascular invasion, bone marrow formation and endochondral ossification.

    DOI: 10.1242/dev.045203

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  • 軟骨特異的CCN2/CTGF過剰発現による膝関節軟骨の加齢に伴う変性抑制効果

    伊藤慎将, 伊藤慎将, 服部高子, 冨田奈緒, 冨田奈緒, 青山絵理子, 山城隆, 滝川正春

    日本軟骨代謝学会プログラム・抄録集   23rd   2010

  • CCN2/CTGFの核内移行とExportin-1による核-細胞質間分子輸送

    服部高子, 星島光博, 荒木大介, 青山絵理子, 滝川正春

    日本骨代謝学会学術集会プログラム抄録集   28th   259 - 259   2010

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  • CCN2/CTGFはマトリリン-3と結合して軟骨マトリックス成分のネットワーク形成を促進する

    服部高子, 荒木大介, 星島光博, 青山絵理子, 新村兆一郎, OTTEN Christiane, WAGENER Raimund, 滝川正春

    生化学   2010

  • Exportin-1によるCCN2/CTGFの核-細胞質間分子輸送とその生理的意義

    内田瑶子, 服部高子, 荒木大介, 滝川正春

    Journal of Oral Biosciences   52 ( Supplement )   189 - 189   2010

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  • 軟骨組織特異的CCN2/CTGF過剰発現によりマウスの膝関節軟骨は加齢後もより正常に近い形質を維持する

    伊藤慎将, 伊藤慎将, 服部高子, 山城隆, 滝川正春, 滝川正春

    Journal of Oral Biosciences   52 ( Supplement )   136 - 136   2010

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  • CCN2/CTGFとCCN2/CTGF,およびCCN3/NOVとの結合とそれらの相互作用の解析

    星島光博, 星島光博, 服部高子, 青山絵理子, 西田崇, 山城隆, 滝川正春

    岡山歯学会雑誌   29 ( 1 )   74 - 74   2010

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  • CCN2/CTGFはマトリリン-3と結合して軟骨マトリックス成分のネットワーク形成を促進する

    服部高子, 荒木大介, 星島光博, 青山絵理子, 新村兆一郎, OTTEN Christiane, WAGENER Raimund, 滝川正春

    日本結合組織学会学術大会抄録集   42nd   1P - 0290   2010

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  • CCN2/CTGFのホモダイマー形成,およびCCN3/NOVとのヘテロダイマーの形成とそれらの軟骨細胞における生理作用

    星島光博, 星島光博, 服部高子, 青山絵理子, 西田崇, 山城隆, 滝川正春

    日本骨代謝学会学術集会プログラム抄録集   28th   260 - 260   2010

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  • Sox9は血管侵入,骨髄形成および内軟骨性骨形成の最終段階を抑制する-Col10a1-BACトランスジェニックマウスを用いた解析-

    服部高子, 池側広志, 小郷絢子, 滝川正春

    日本軟骨代謝学会プログラム・抄録集   23rd   2010

  • CCN2/CTGFのホモダイマー形成,およびCCN3/NOVとのヘテロダイマーの形成と,それらが軟骨細胞の基質合成に及ぼす役割

    星島光博, 星島光博, 星島光博, 服部高子, 青山絵理子, 西田崇, 山城隆, 滝川正春

    生化学   83回・33回   2P - 0101   2010

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  • 軟骨組織特異的CCN2/CTGF過剰発現による膝関節軟骨の加齢変性抑制効果

    伊藤慎将, 伊藤慎将, 服部高子, 青山絵理子, 山城隆, 滝川正春

    生化学   83回・33回   4P - 1007   2010

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  • 軟骨特異的転写因子Sox9のSUMO化による活性調節機構の解明

    服部 高子

    岡山歯学会雑誌   28 ( 1 )   82 - 82   2009.6

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  • CCN2/CTGF has anti-aging effects to protect articular cartilage from age-related degenerative changes

    S. Itoh, T. Hattori, N. Tomita, E. Aoyama, T. Yamashiro, M. Takigawa

    BONE   44   S47 - S47   2009.5

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    DOI: 10.1016/j.bone.2009.01.121

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  • Sox9は軟骨において血管侵入を抑制する事によって内軟骨性骨形成の最終段階である骨髄形成を抑制する-Col10a1-BACトランスジェニックマウスを用いた解析-

    服部高子, 池側広志, 小郷絢子, 滝川正春

    生化学   82回   2P - 745   2009

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  • CCN2/CTGFの軟骨特異的過剰発現は加齢に伴う膝関節軟骨の変性に対して抑制的に働く

    伊藤慎将, 伊藤慎将, 服部高子, 冨田奈緒, 冨田奈緒, 青山絵里子, 青山絵里子, 山城隆, 滝川正春

    日本軟骨代謝学会プログラム・抄録集   22nd   2009

  • 軟骨特異的CCN2/CTGF過剰発現は関節軟骨を加齢に伴う変形性関節炎様変化から防御する

    伊藤慎将, 伊藤慎将, 服部高子, 冨田奈緒, 冨田奈緒, 青山絵理子, 山城隆, 滝川正春

    日本骨代謝学会学術集会プログラム抄録集   27th   249 - 249   2009

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  • 軟骨特異的CCN2/CTGF過剰発現マウスは膝関節軟骨の加齢に伴う変形性関節症様軟骨変化が抑制され,より正常に近い形質を維持する

    伊藤慎将, 伊藤慎将, 服部高子, 冨田奈緒, 青山絵里子, 山城隆, 滝川正春

    日本分子生物学会年会講演要旨集   32nd ( Vol.4 )   2009

  • CCN2/CTGFと結合するタンパク質の同定

    星島光博, 服部高子, 荒木大介, 青山絵理子, 西田崇, 滝川正春

    岡山歯学会雑誌   28 ( 1 )   93 - 94   2009

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  • CCN2/CTGFのExportin-1による核-細胞質間分子輸送

    服部高子, 小郷絢子, 圓城裕基, 池側広志, 荒木大介, 星島光博, 青山絵理子, 滝川正春

    日本分子生物学会年会講演要旨集   32nd ( Vol.1 )   2009

  • 軟骨特異的CCN2/CTGF過剰発現は膝関節軟骨を加齢に伴う変性から保護する

    伊藤慎将, 伊藤慎将, 服部高子, 青山絵里子, 山城隆, 滝川正春

    Journal of Oral Biosciences   51 ( Supplement )   105 - 105   2009

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  • 軟骨特異的CCN2/CTGF過剰発現マウスは膝関節軟骨の加齢性変化に抵抗性を示す

    伊藤慎将, 服部高子, 冨田奈緒, 青山絵里子, 山城隆, 滝川正春

    生化学   82回   2T5a - 4   2009

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  • Specific expression of Cre recombinase in hypertrophic cartilage under the control of a BAC-Col10a1 promoter

    Sonja Gebhard, Takako Hattori, Eva Bauer, Britta Schlund, Michael R. Boesl, Benoit de Crombrugghe, Klaus von der Mark

    MATRIX BIOLOGY   27 ( 8 )   693 - 699   2008.10

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    Previously we have shown that insertion of a LacZ reporter gene into the Col10a1 gene in the context of a bacterial artificial chromosome (BAC) drives strong and specific expression of LacZ in hypertrophic cartilage of transgenic mice [Gebhard S., Hattori T, Bauer E., Bosl M.R., Schlund B., Poschl E., Adam N., de Crombrugghe B., von der Mark K., 2007 Histochem. Cell Biol. 19 127:183-194]. BAC constructs in transgenic reporter mouse lines control efficient and specific LacZ expression in hypertrophic chondrocytes under the complete Col10a1 promoter. Here we report on the generation of Col10a1-specific Cre deleter mice using a BAC recombineering technique based on homologous recombination in E. coli. Sixteen BAC-Col10-Cre transgenic lines were generated containing between I and 5 copies of the BAC-Col10-Cre gene. All lines tested so far expressed Cre specifically in hypertrophic chondrocytes of E16.5 and PI growth plates of long bones, ribs, vertebrae and sternum as examined by crossing with ROSA26 reporter mice. Cre activity was detected as early as E13.5 when hypertrophic cartilage develops in the diaphysis of femur and humerus. The data confirm that expression of Cre under the control of the complete BAC-Col10a1 promoter occurs with high efficiency and specificity in hypertrophic chondrocytes. The BAC-Col10-Cre lines should thus provide a Valuable tool to get further insight into the role of genes involved in endochondral ossification by allowing their specific deletion in the hypertrophic zone of the growth plate. (C) 2008 Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.matbio.2008.07.001

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  • Overexpression of CCN2/CTGF in Cartilage Shows Prolonged Bone Length Resulting from Stimulation of Chondrogenesis, Chondrocyte Growth, Apoptosis, and Bone Mineralization During Endochondral Ossification.

    N. Tomita, T. Hattori, S. Ito, E. Aoyama, M. Yao, T. Yamashiro, M. Takigawa

    JOURNAL OF BONE AND MINERAL RESEARCH   23   S411 - S411   2008.9

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  • Transcriptional regulation of chondrogenesis by coactivator Tip60 via chromatin association with Sox9 and Sox5

    Takako Hattori, Francoise Coustry, Shelley Stephens, Heidi Eberspaecher, Masaharu Takigawa, Hideyo Yasuda, Benoit de Crombrugghe

    NUCLEIC ACIDS RESEARCH   36 ( 9 )   3011 - 3024   2008.5

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    Sox9 is a transcription factor of the SRY family required for several steps of chondrogenesis. It activates the expression of various chondrocyte-specific genes, but the mechanisms and role of cofactors involved in Sox9-regulated gene transcription are not fully understood. Here, we report on the characterization of a Tat interactive protein-60 (Tip60) as Sox9-associated protein identified in a yeast two-hybrid screen. Both in vitro and in vivo assays confirmed the specificity of interactions between Sox9 and Tip60 including the existence of an endogenous complex containing both polypeptides in chondrocytes. Gel shift assays showed the presence of a complex containing Sox9, Tip60 and the DNA of an enhancer region of the Col2a1 promoter. Reporter assays using a Col2a1 promoter with multimerized Col2a1 Sox9-binding sites indicated that Tip60 enhanced the transcriptional activity of Sox9. A larger Col2a1 promoter showed that Tip60 increased the activity of this promoter in the presence of both Sox9 and Sox5. Ectopic expression of Sox9 and transient-cotransfection with Tip60 in COS7 cells showed a more diffuse subnuclear colocalization, suggesting changes in the chromatin structure. Chromatin immunoprecipitation assays showed that Tip60, Sox9 and Sox5 associated with the same Col2a1 enhancer region. Consistent with a role of Tip60 in chondrogenesis, addition of Tip60 siRNA to limb-bud micromass cultures delayed chondrocyte differention. Tip60 enhances acetylation of Sox9 mainly through K61, 253, 398 residues; however, the K61/253/398A mutant of Sox9 still exhibited enhanced transcriptional activity by Tip60. Our results support the hypothesis that Tip60 is a coactivator of Sox9 in chondrocytes.

    DOI: 10.1093/nar/gkn150

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  • CCN2/CTGF軟骨特異的過剰発現マウスの作製とその硬組織の解析

    冨田奈緒, 冨田奈緒, 服部高子, 伊藤慎将, 伊藤慎将, 青山絵里子, 青山絵里子, 矢尾真弓, 山城隆, 滝川正春

    生化学   80 ( 7 )   694 - 694   2008

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  • CCN2/CTGFの軟骨特異的過剰発現が内軟骨性骨化に及ぼす影響

    冨田奈緒, 冨田奈緒, 服部高子, 伊藤慎将, 伊藤慎将, 青山絵理子, 青山絵理子, 矢尾真弓, 山城隆, 滝川正春

    日本骨代謝学会学術集会プログラム抄録集   26th   168 - 168   2008

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  • 軟骨成長・分化因子CCN2/CTGFはマトリリン3に結合する事によってマトリックスのネットワーク形成を促進する

    荒木大介, 服部高子, 青山絵理子, 星島光博, 滝川正春

    Journal of Oral Biosciences   50 ( Supplement )   179 - 179   2008

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  • 軟骨特異的CCN2/CTGF過剰発現は骨延長を誘導する

    服部高子, 冨田奈緒, 冨田奈緒, 伊藤慎将, 伊藤慎将, 青山絵理子, 矢尾真弓, 山城隆, 滝川正春

    生化学   2008

  • CCN2/CTGFの関節軟骨アンチエイジング作用:軟骨組織特異的CCN2/CTGF過剰発現マウスを用いた解析

    伊藤慎将, 伊藤慎将, 服部高子, 冨田奈緒, 冨田奈緒, 青山絵理子, 青山絵理子, 山城隆, 滝川正春

    日本骨代謝学会学術集会プログラム抄録集   26th   177 - 177   2008

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  • CCN2/CTGFの軟骨特異的過剰発現マウスモデルの作製と解析

    冨田奈緒, 冨田奈緒, 服部高子, 伊藤慎将, 伊藤慎将, 青山絵理子, 青山絵理子, 矢尾真弓, 山城隆, 滝川正春

    日本軟骨代謝学会プログラム・抄録集   21st   2008

  • CCN2/CTGF軟骨特異的過剰発現が骨格形成に及ぼす影響

    冨田奈緒, 冨田奈緒, 服部高子, 伊藤慎将, 伊藤慎将, 青山絵理子, 山城隆, 滝川正春

    Journal of Oral Biosciences   50 ( Supplement )   148 - 148   2008

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  • 結合組織成長因子(CCN2/CTGF)とアグリカンとの結合についての解析(Analysis of binding between CCN2/CTGF and aggrecan)

    青山 絵理子, 服部 高子, 荒木 大介, 星島 光博, 滝川 正春

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   80回・30回   2T22 - 13   2007.11

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  • BAC constructs in transgenic reporter mouse lines control efficient and specific LacZ expression in hypertrophic chondrocytes under the complete Col10a1 promoter

    Sonja Gebhard, Takako Hattori, Eva Bauer, Michael R. Boesl, Britta Schlund, Ernst Poeschl, Nadia Adam, Benoit de Crombrugghe, Klaus von der Mark

    HISTOCHEMISTRY AND CELL BIOLOGY   127 ( 2 )   183 - 194   2007.2

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    During endochondral ossification hypertrophic chondrocytes in the growth plate of fetal long bones, ribs and vertebrae play a key role in preparing growth plate cartilage for replacement by bone. In order to establish a reporter gene mouse to facilitate functional analysis of genes expressed in hypertrophic chondrocytes in this process, Col10a1- BAC reporter gene mouse lines were established expressing LacZ specifically in hypertrophic cartilage under the control of the complete Col10a1 gene. For this purpose, a bacterial artificial chromosome (BAC RP23-192A7) containing the entire murine Col10a1 gene together with 200 kb flanking sequences was modified by inserting a LacZ-Neo cassette into the second exon of Col10a1 by homologous recombination in E. coli. Transgenic mice containing between one and seven transgene copies were generated by injection of the purified BAC-Col10a1- lLacZ DNA. X-gal staining of newborns and embryos revealed strong and robust LacZ activity exclusively in hypertrophic cartilage of the fetal and neonatal skeleton of the transgenic offspring. This indicates that expression of the reporter gene in its proper genomic context in the BAC Col10a1 environment is independent of the integration site and reflects authentic Col10a1 expression in vivo. The Col10a1 specific BAC recombination vector described here will enable the specific analysis of effector gene functions in hypertrophic cartilage during skeletal development, endochondral ossification, and fracture callus healing.

    DOI: 10.1007/s00418-006-0236-8

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  • 結合組織成長因子CTGF/CCN2 (Connective tissue growth factor (CTGF)/CCN2)

    服部高子, 久保田聡, 滝川正春

    The Lung perspectives   15 ( 3 )   331 - 335   2007

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    結合組織成長因子(connective tissue growth factor;CTGF/CCN2)は前肥大軟骨細胞層が特異的に発現する遺伝子として、また、血管内皮細胞の培養上清中に存在する線維芽細胞の増殖・遊走促進因子として単離されたが、その発現部位は軟骨組織、血管内皮細胞だけでなく、脳をはじめとする神経系にも広がり、また、血小板に大量に蓄積されて体内を循環している。生理的には、正常な内軟骨性骨形成、血管新生、胚発育に必須であることが明らかになっており、細胞外マトリックス成分の合成を強く促進し、細胞外マトリックスに富む軟骨組織で高発現していることと密接に関連している。また、肺をはじめ、心臓、肝臓、腎臓、筋、膵臓などの組織における線維芽細胞では、トランスフォーミング増殖因子(TGF)-βの誘導に伴って遺伝子発現が誘導され、各組織の線維化、線維症の形成を促進することから、そのメディエーターとしての働きが注目されている。また、乳癌細胞で高度に発現していることが観察されているが、低酸素状態によってCTGF/CCN2の発現が誘導され、これにより血管新生が惹起されることが明らかになっている。(著者抄録)

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  • 結合組織成長因子(CCN2/CTGF)とアグリカンとの結合の生理的意義の解析

    青山絵理子, 服部高子, 荒木大介, 星島光博, 滝川正春

    日本骨代謝学会学術集会プログラム抄録集   25th   237 - 237   2007

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  • Tip60によるSox9,Sox5のクロマチンを介した軟骨分化の制御

    服部高子, 滝川正春

    日本骨代謝学会学術集会プログラム抄録集   25th   190 - 190   2007

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  • 結合組織成長因子(CCN2/CTGF)結合タンパク質の同定および軟骨細胞におけるその結合の生理的意義

    青山絵里子, 荒木大介, 星島光博, 服部高子, 滝川正春

    日本軟骨代謝学会プログラム・抄録集   20th   2007

  • 軟骨特異的にCCN2/CTGFを過剰発現したトランスジェニックマウスの作製と解析

    冨田奈緒, 冨田奈緒, 服部高子, 矢尾真弓, 青山絵理子, 山城隆, 滝川正春

    生化学   80回・30回   2T6 - 2   2007

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  • 軟骨特異的CCN2/CTGF過剰発現トランスジェニックマウスの作製とCCN2/CTGFの内軟骨性骨化に及ぼす影響について

    冨田奈緒, 冨田奈緒, 服部高子, 青山絵理子, 青山絵理子, 山城隆, 滝川正春

    Journal of Oral Biosciences   49 ( Supplement )   125 - 125   2007

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  • CCN2はフィブロネクチン及びマトリリン3と相互作用し,軟骨細胞の接着および細胞外マトリックスの重合を制御している

    星島光博, 服部高子, 荒木大介, 青山絵理子, 滝川正春

    岡山歯学会雑誌   26 ( 1 )   53 - 54   2007

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  • 軟骨細胞において結合組織成長因子/CCNファミリー2(CTGF/CCN2)はHIF-1αの発現を介してVEGF発現を制御する

    西田崇, 久保田聡, 前田あずさ, 前田あずさ, 服部高子, 川木晴美, 滝川正春

    日本軟骨代謝学会プログラム・抄録集   20th   2007

  • 軟骨成長・分化因子CCN2/CTGFとMatrilin3の相互作用

    荒木大介, 服部高子, 青山絵理子, 星島光博, 滝川正春

    Journal of Oral Biosciences   49 ( Supplement )   198 - 198   2007

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  • CCN2/CTGF過剰発現トランスジェニックマウスの作製によるCCN2/CTGFの内軟骨性骨化における役割解明

    冨田奈緒, 冨田奈緒, 服部高子, 矢尾真弓, 山城隆, 滝川正春

    日本骨代謝学会学術集会プログラム抄録集   25th   247 - 247   2007

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  • COPDと気管支喘息-接点の問題-基礎医学とのダイアローグ 結合組織成長因子CTGF/CCN2

    服部高子, 久保田聡, 滝川正春

    Lung Perspectives   15 ( 3 )   2007

  • Twisted gastrulation modulates bone morphogenetic protein-induced collagen II and X expression in chondrocytes in vitro and in vivo International journal

    Martina Schmidl, Nadia Adam, Cordula Surmann-Schmitt, Takako Hattori, Michael Stock, Uwe Dietz, Benoit de Crombrugghe, Ernst Poeschl, Klaus von der Mark

    JOURNAL OF BIOLOGICAL CHEMISTRY   281 ( 42 )   31790 - 31800   2006.10

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    Twisted gastrulation (TSG) is an extracellular modulator of bone morphogenetic protein (BMP) activity and regulates dorsoventral axis formation in early Drosophila and Xenopus development. Studies on tsg-deficient mice also indicated a role of this protein in skeletal growth, but the mechanism of TSG activity in this process has not yet been investigated. Here we show for the first time by in situ hybridization and immunohistochemistry that TSG is strongly expressed in bovine and mouse growth plate cartilage as well as in fetal ribs, vertebral cartilage, and cartilage anlagen of the skull. Furthermore we provide evidence that TSG is directly involved in BMP-regulated chondrocyte differentiation and maturation. In vitro, TSG impaired the dose-dependent BMP-2 stimulation of collagen II and X expression in cultures of MC615 chondrocytes and primary mouse chondrocytes. In the presence of chordin, a BMP antagonist, the inhibitory effect of TSG was further enhanced. TSG also inhibited BMP2-stimulated phosphorylation of Smad factors in chondrocytes, confirming the role of TSG as a modulator of BMP signaling. For analysis of TSG functions in cartilage development in vivo, the gene was overexpressed in transgenic mice under the control of the cartilage-specific Col2a1 promoter. As a result, Col10a1 expression was significantly reduced in the growth plates of transgenic embryos and newborns in comparison with wild type littermates as shown by in situ hybridization and by real time PCR analysis. The data suggest that TSG is an important modulator of BMP-regulated cartilage development and chondrocyte differentiation.

    DOI: 10.1074/jbc.M603419200

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  • Interactions between PIAS proteins and SOX9 result in an increase in the cellular concentrations of SOX9

    Takako Hattori, Heidi Eberspaecher, Jingfang Lu, Ren Zhang, Tamotsu Nishida, Tomoaki Kahyo, Hideyo Yasuda, Benoit de Crombrugghe

    JOURNAL OF BIOLOGICAL CHEMISTRY   281 ( 20 )   14417 - 14428   2006.5

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    We have identified PIAS1 (protein inhibitor of activated STAT-1), -3, -x alpha, and -x beta as SOX9-associated polypeptides using the Gal4-based yeast two-hybrid system and a cDNA library derived from a chondrocytic cell line. These PIAS proteins were shown to interact directly with SOX9 in two-hybrid, co-immunoprecipitation, and electrophoretic mobility shift assays. SOX9 was sumoylated in cotransfection experiments with COS-7 cells using PIAS and SUMO-1 (small ubiquitin-like modifier-1) expression vectors. SOX9 was also sumoylated in vitro by PIAS proteins in the presence of SUMO-1, the SUMO-activating enzyme, and the SUMO-conjugating enzyme. In COS-7 cells, PIAS proteins stimulated the SOX9-dependent transcriptional activity of a Col2a1 promoter-enhancer reporter. This increase in reporter activity was paralleled by an increase in the cellular levels of SOX9. Cotransfection with a SUMO-expressing vector further enhanced the transcriptional activity of this SOX9-dependent Col2a1 reporter in COS-7 cells, and this additional activation was inhibited in the presence of either SUMO-1 mutants or PIAS RING domain mutants or by coexpression of a desumoylation enzyme. Immunofluorescence microscopy of SOX9-transfected COS-7cells showed that the subnuclear distribution of SOX9 became more diffuse in the presence of PIAS1 and SUMO-1. Our results suggest that, by controlling the cellular concentrations of SOX9, PIAS proteins and sumoylation may be part of a major regulatory system of SOX9 functions.

    DOI: 10.1074/jbc.M511330200

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  • 関節リウマチ上肢病変/関節リウマチ下肢病変/生物学的製剤と手術 関節リウマチ後足部扁平変形のX線学的解析

    服部 高子, 菅本 一臣, 橋本 淳, 冨田 哲也, 北村 卓司, 吉川 秀樹

    日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集   50回・15回   203 - 203   2006.3

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  • 関節リウマチの画像診断 リウマチ肘における関節破壊のX線学的検討

    北村 卓司, 菅本 一臣, 橋本 淳, 村瀬 剛, 服部 高子, 吉川 秀樹

    日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集   50回・15回   131 - 131   2006.3

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  • 関節リウマチにおける自己抗原と分子シャペロン-軟骨細胞におけるその役割

    服部高子, 滝川正春

    Clinical Calcium   16,1553-1556 ( 9 )   1553 - 1556   2006

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    小胞体シャペロンheat shock protein/rheumatoid arthritis-related antigen(HSP47/RA-A47)は細胞内のコラーゲン成熟、分泌の機能を持ち、細胞をストレスから防御し、未成熟あるいは正常な合成に失敗したコラーゲンの細胞外への分泌を妨げる役割を担っているが、リウマチ軟骨ではその発現量が減少しており、細胞に小胞体ストレスを誘発している。また、軟骨細胞破壊につながる細胞障害性因子の放出を促し、その結果軟骨細胞はアポトーシスにより死ぬ。また、この時細胞外にHSP47/RA-A47が放出される。細胞外HSP47/RA-A47は自己抗原として認識される可能性があるが、抗原抗体反応およびそれにかかわる炎症反応を制御している可能性もある。HSP47/RA-A47の細胞内外の量のコントロールがリウマチ治療の鍵となろう。(著者抄録)

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  • Connective tissue growth factor (CTGF/CCN2) reinforces the molecular phenotype of aauricular chondrocytes in vitro.

    T Fujisawa, K Nakao, T Hattori, S Kubota, T Kuboki, M Takigawa

    JOURNAL OF BONE AND MINERAL RESEARCH   20 ( 9 )   S197 - S197   2005.9

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  • ヒト軟骨肉腫由来軟骨細胞株 (HCS-2/8)におけるWnt誘導分泌タンパク質1 (Wisp1/CCN4)mRNAスプライス変異体(Writ-induced secreted protein 1(Wispl/CCN4) mRNA splicing variants in a human chondrosarcoma-derived chondrocytic cell line (HCS-2/8))

    Yanagita Takeshi, Kubota Satoshi, Hattori Takako, Hoshijima Mitsuhiro, Kawata Kazumi, Takano-Yamamoto Teruko, Takigawa Masaharu

    生化学   77 ( 8 )   1014 - 1014   2005.8

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  • 関節リウマチにおける肘関節破壊様式のX線学的検討

    北村 卓司, 菅本 一臣, 服部 高子, 森友 寿夫, 冨田 哲也, 村瀬 剛, 橋本 淳, 吉川 秀樹

    日本整形外科学会雑誌   79 ( 3 )   S44 - S44   2005.3

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  • Downregulation of rheumatoid arthritis-related antigen RA-A47 (HSP47/colligin-2) in chondrocytic cell lines induces apoptosis and cell-surface expression of RA-A47 in association with CD9 International journal

    T Hattori, K von der Mark, H Kawaki, Y Yutani, S Kubota, T Nakanishi, H Eberspaecher, B de Crombrugghe, M Takigawa

    JOURNAL OF CELLULAR PHYSIOLOGY   202 ( 1 )   191 - 204   2005.1

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    Previously, we showed that gene expression of the rheurnatoid arthritis-related antigen RA-A47, which is identical to human heat shock protein (HSP)47, was downregulated in chondrocytes by inflammatory cytokines such as TNFalpha. Associated with this phenomenon, RA-A47 appeared on the cell surface concomitant with upregulation of metabolic factors related to cartilage destruction. The upregulation of the metabolic factors could be achieved by clownregulation of RA-A47 expression with ra-a47-specific anti-senseoligonucleotide. Here, we show that the enhanced surface expression of RA-A47 on a chondrocytic cell line, HCS-2/ 8 was also a direct result of RA-A47 downregulation by ra-a47 anti-sense oligonucleoticle, independent of the cytokine effects. Moreover, cell-surface expression of CD9, a l integrin-associated transmembrane protein that is involved in cell adhesion and cell motility events, was enhanced in the ra-a47 anti-sense oligonucleoticle-treated cells. The CD9 was colocalized with RA-A47 on the cell surface, where it may have affected integrin signaling. Furthermore, Annexin-V binding to the cell surface and the level of a number of apoptosis-related genes including caspase-9 were increased after ra-a47 anti-sense oligonucleoticle treatment, suggesting that enhanced surface expression of RA-A47 and CD9 may be initiating apoptosis. Differential screening using a cDNA gene array showed induction of metal lothionein-III and chemokine receptor CXCR4 and of factors of the Notch signaling pathway by the anti-sense treatment, but not by TNFalpha.. Thus, here we show for the first time an alternative mechanism of inducing apoptosis by downregulating molecular chaperones, independent of the action of TNFalpha. The surface-exposed RA-A47 may induce autoantibodies and inflammatory reactions in autoimmune disease situations such as rheurnatoid arthritis. J. Cell. Physiol. 202: 191 -204, 2005. (C) 2004 Wiley-Liss, Inc.

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  • 転写因子SOX9,p53の活性制御機構-SUMO化との関連は?

    安田秀世, 巻さゆみ, 滝川正春, 服部高子

    日本分子生物学会年会講演要旨集   28th   2005

  • 軟骨由来多機能成長因子CCN2/CTGF/Hcs24は耳介軟骨細胞の形質発現を増強する

    藤澤拓生, 藤澤拓生, 中尾匡志, 服部高子, 久保田聡, 窪木拓男, 滝川正春

    日本骨代謝学会学術集会プログラム抄録集   23rd   262 - 262   2005

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  • 関節炎と軟骨(1)2 コラーゲン特異的分子シャペロンHSP47/RA-A47の発現量低下が軟骨細胞の破壊とHSP47/RA-A47の細胞表面への露出を引き起こす:関節リウマチにおける自己抗原としての認識機構

    服部高子, VON DER MARK Klaus, 川木晴美, 油谷安孝, 久保田聡, 中西徹, DE CROMBRUGGHE Benoit, 滝川正春

    日本軟骨代謝学会プログラム・抄録集   18th   2005

  • 転写活性化因子Tip60のSox9,Sox5複合体への会合を介した軟骨分化の制御

    服部高子, 服部高子, 安田秀世, 滝川正春, DE CROMBRUGGHE Benoit

    日本分子生物学会年会講演要旨集   28th   2005

  • CCN2/CTGFはコラーゲン特異的分子シャペロンHSP47/リウマチ関連抗原RA-A47の発現量を減少させる-リウマチ病態および軟骨組織の修復との関連-

    矢尾真弓, 矢尾真弓, 服部高子, 川木晴美, 油谷安孝, 滝川正春

    日本骨代謝学会学術集会プログラム抄録集   23rd   168 - 168   2005

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  • デキサメタゾン刺激はCCN2/CTGFの誘導を介して軟骨細胞のリウマチ関連抗原HSP47/RA-A47の発現量を減少させる リウマチ病態および軟骨組織の修復との関連性について

    矢尾真弓, 矢尾真弓, 服部高子, 川木晴美, 久保田聡, 油谷安孝, 佐々木朗, 滝川正春

    Journal of Oral Biosciences   47 ( Supplement )   86 - 86   2005

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  • 成長因子 2 耳介軟骨細胞に対する結合組織成長因子(CTGF/CCN2)の効果

    藤沢拓生, 中尾匡志, 服部高子, 久保田聡, 窪木拓男, 滝川正春

    日本軟骨代謝学会プログラム・抄録集   18th   2005

  • 関節炎と軟骨(2)4 変形性関節症においても,2型腫よう壊死因子可溶性受容体は関節破壊や炎症を調節する

    上原淳二, 藤沢拓生, 大野充昭, 前川賢治, 服部高子, 滝川正春, 窪木拓男

    日本軟骨代謝学会プログラム・抄録集   18th   2005

  • A highly conserved enhancer in mammalian type X collagen genes drives high levels of tissue-specific expression in hypertrophic cartilage in vitro and in vivo International journal

    S Gebhard, E Poschl, S Riemer, E Bauer, T Hattori, H Eberspaecher, ZP Zhang, Lefebvre, V, B de Crombrugghe, K von der Mark

    MATRIX BIOLOGY   23 ( 5 )   309 - 322   2004.8

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    Previously we have identified a cis-acting regulatory domain in the human type X collagen gene upstream of the transcription start site which acts as a strong enhancer in hypertrophic, but not in resting chondrocytes. Here we show that this enhancer is highly conserved also in the murine and bovine Col10a1 genes, but not found in the known promoter sequences of chicken COllOal. It contains a functionally active AP-1 site (TPA Responsive Element, TRE) which is essential for the high transcriptional activity of the COL10A1 enhancer in transiently transfected hypertrophic chondrocytes. Gel-shift experiments with nuclear extracts of hypertrophic chondrocytes revealed FosB and Fra-1 as candidates regulating AP-1 factors binding to the THE site. In fact, coexpression of FosB and Fra-1 in reporter gene assays greatly stimulated transcriptional activity of enhancer bearing reporter genes. Quantitative analysis of AP-1 factor mRNA levels in distinct fractions of fetal bovine epiphyseal chondrocytes by real-time PCR confirmed significant levels of FosB and Fra-1 mRNA besides other AP-1 factors in hypertrophic chondrocytes.
    A key role of the enhancer element in regulating tissue-specific expression of the Col10a1 gene was shown by establishing transgenic mouse lines with a reporter gene containing a 4.6 kb murine Col10al promoter fragment which included the enhancer, exon 1, part of exon 2 and the first intron. Reporter gene expression was seen exclusively in hypertrophic cartilages in the growth plates of long bones, ribs, vertebrae, sternum and mandibles of 17.5-18.5 dpc embryos, confirming that the 4.6 kb promoter is able to drive specific expression of Col10al in hypertrophic cartilage. These established transgenic lines should facilitate the genetic analysis of regulatory pathways of chondrocyte maturation and Co110al gene expression in the future. (C) 2004 Elsevier B.V/ International Society of Matrix Biology. All rights reserved.

    DOI: 10.1016/j.matbio.2004.05.010

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  • コラーゲン特異的分子シャペロンRA-A47/HSP47:関節リウマチにおける自己抗原としての認識機構

    服部高子, 川木晴美, 油谷安孝, 久保田聡, 中西徹, 滝川正春

    日本骨代謝学会学術集会プログラム抄録集   22nd   230 - 230   2004

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  • 癌抑制遺伝子産物p53のSUMO化の意義

    服部高子, 西田有, 華表友暁, 滝川正春, 巻さゆみ, 上野憲道, DECROMBRUGGHE B, 安田秀世

    日本分子生物学会年会プログラム・講演要旨集   27th   2004

  • Repair of articular cartilage defect by autologous bone marrow mesenchymal cell Transplantation

    服部高子, 脇谷滋之

    関節外科   23 ( 5 )   2004

  • 軟骨特異的転写因子Sox9のSUMO化による活性調節

    服部高子, 西田有, 華表友暁, 滝川正春, DE CROMBRUGGHE B, 安田秀世

    日本分子生物学会年会プログラム・講演要旨集   27th   2004

  • 軟骨細胞における関節リウマチ関連抗原RA-A47の発現抑制による軟骨破壊因子の誘導とRA-A47自身の細胞表面への露出

    服部高子, 久保田聡, 油谷安孝, 中西徹, 滝川正春

    日本リウマチ学会総会・学術集会抄録集   48th   164 - 164   2004

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  • Downregulation of a rheumatoid arthritis-related antigen (RA-A47) by ra-a47 antisense oligonucleotides induces inflammatory factors in chondrocytes Reviewed International journal

    T Hattori, H Kawaki, S Kubota, Y Yutani, B De Crombrugghe, K Von Der Mark, M Takigawa

    JOURNAL OF CELLULAR PHYSIOLOGY   197 ( 1 )   94 - 102   2003.10

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    Previously we have shown that the expression of RA-A47 (rheumatoid arthritis-related antigen) which is identical to HSP47, a collagen-binding chaperon, is downregulated in chondrocytes by tumor necrosis factor alpha (TNFalpha). RA-A47 was also found on the surface of chondrocytes where it is recognized as an antigen in the serum of rheumatoid arthritis (RA) patients. Its translocation to the cell surface from endoplasmic reticulum membrane where it is normally located was also enhanced by TNFalpha. To understand the significance of RA-A47 downregulation in chondrocytes independent from other effects of TNFalpha, we used an antisense oligonucleotide approach and investigated the effect of this treatment on the expression of molecules related to matrix degradation and production of growth factors for chondrocytic, endothelial, and synovial cells. Here we show that treatment of rabbit chondrocyes and human chondrosarcoma cells HCS-2/8 by ra-a47 antisense S-oligonucleotides significantly reduced the expression of ra-a47 both at mRNA and protein level. Interestingly, this TNFalpha-independent RA-A47 clownregulation was associated with a strong induction of matrix metalloproteinase (MMP)-9 mRNA and inducible NO synthase (iNOS) mRNA. The induction of active-type MMP-9 was further detected by gelatin zymography. Under the same conditions, the release of basic fibroblast growth factor (bFGF) and connective tissue growth factor (CTGF) from HCS-2/8 cells into the conditioned medium (CM) was strongly enhanced. These effects were not a result of TNFalpha upregulation, since the ra-a47 antisense oligonucleotide treatment did not enhance TNFalpha synthesis. These observations indicate that clownregulation of RA-A47 induces TNFalpha-independent cartilage-degrading pathways involving iNOS and MMP-9. Furthermore, the stimulation of bFGF and CTGF release from chondrocytes may stimulate the proliferation of adjacent endothelial and/or synovial cells. (C) 2003 Wiley-Liss, Inc.

    DOI: 10.1002/jcp.10341

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  • 変形性関節症滑膜に発現されたmRNAの,ランダムシークエンス法による解析

    脇谷滋之, 服部高子, 大森義裕, 菱垣晴次, 谷上信, 菅野純夫

    リウマチ   43 ( 2 )   2003

  • CTGF/Hcs24 induces chondrocyte differentiation through p38 mitogen-activated protein kinase (p38MAPK), and proliferation through p44/42 MAPK/extracellular-signal regulated kinase (ERK).

    G Yosimichi, T Nakanishi, T Nishida, T Hattori, T Takano-Yamamoto, M Takigawa

    JOURNAL OF BONE AND MINERAL RESEARCH   17   S222 - S223   2002.9

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  • 結合組織成長因子(CTGF)の構造・機能解析のためのELISAシステムの開発

    川木 晴美, 久保田 聡, 湊 雅直, 森谷 徳文, 服部 高子, 大山 和美, 中西 徹, 滝川 正春

    岡山歯学会雑誌   21 ( 1 )   182 - 183   2002.6

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  • 結合組織成長因子CTGF/Hcs24は細胞内で細胞骨格蛋白質と結合する

    吉道玄, 久保田聡, 服部高子, 西田崇, 縄稚久美子, 中西徹, 山本照子, 滝川正春

    生化学   74 ( 8 )   797 - 797   2002

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  • ウサギ変形性顎関節症モデルにおける軟骨細胞アポトーシスの関与

    藤沢拓生, 笠井照夫, 窪木拓男, 矢谷博文, 服部高子, 滝川正春

    日本顎関節学会雑誌   14 ( 1 )   110 - 110   2002

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  • 関節軟骨再生と組織工学

    服部高子

    臨床検査   46 ( 4 )   403 - 406   2002

  • 再生医療 骨と軟骨 関節軟骨の再生

    服部高子, 脇谷滋之

    Clinical Calcium   12 ( 2 )   2002

  • 遺伝子発現の抑圧的調節を仲介するマウスctgf3'-UTR segmentの性質

    近藤 誠二, 久保田 聡, 江口 傑徳, 服部 高子, 中西 徹, 菅原 利夫, 滝川 正春

    日本口腔科学会雑誌   50 ( 6 )   568 - 568   2001.11

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  • 軟骨由来成長因子CTGF/Hcs24遺伝子の転写後制御エレメントCAESARの構造と機能

    久保田 聡, 近藤 誠二, 江口 傑徳, 服部 高子, 中西 徹, 滝川 正春

    歯科基礎医学会雑誌   43 ( 5 )   554 - 554   2001.8

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  • 自己骨髄間葉系細胞移植による関節軟骨欠損修復

    脇谷 滋之, 山本 鉄也, 井本 一彦, 服部 高子, 斉藤 正伸, 村田 紀和

    日本整形外科学会雑誌   75 ( 8 )   S1028 - S1028   2001.8

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  • 軟骨由来成長因子CTGF/Hcs24のヒト軟骨細胞株HCS-2/8におけるプロセシングと分泌の様態

    久保田 聡, 江口 傑徳, 志茂 剛, 西田 崇, 服部 高子, 近藤 誠二, 中西 徹, 滝川 正春

    日本骨代謝学会雑誌   19 ( 2 )   104 - 104   2001.7

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  • 結合組織成長因子CTGF/Hcs24の軟骨細胞様細胞株HCS-2/8での発現と動態制御

    久保田 聡, 江口 傑徳, 志茂 剛, 服部 高子, 近藤 誠二, 中西 徹, 滝川 正春

    Connective Tissue   33 ( 2 )   157 - 157   2001.6

  • 軟骨由来の成長因子(Connective Tissue Growth Factor,CTGF/Hcs24)の軟骨細胞増殖,分化促進作用における情報伝達機構の解析

    吉道玄, 中西徹, 西田崇, 服部高子, 山本照子, 滝川正春

    日本骨代謝学会雑誌   19 ( 2 )   102 - 102   2001

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  • Characterization of a Mouse ctgf3′-UTR Segment that Mediates Repressive Regulation of Gene Expression.

    近藤誠二, 久保田聡, 江口傑徳, 服部高子, 中西徹, 菅原利夫, 滝川正春

    日本口腔科学会雑誌   50 ( 6 )   2001

  • CTGF/Hcs24軟骨強制発現トランスジェニックマウスの解析

    縄稚久美子, 中西徹, 吉道玄, 中田英二, 服部高子, 小守寿文, 滝川正春

    日本骨代謝学会雑誌   19 ( 2 )   30 - 30   2001

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  • 多機能成長因子CTGF/Hcs24遺伝子の転写後制御エレメント,CAESARの作用機序

    久保田聡, 近藤誠二, 椋代義樹, 江口傑徳, 服部高子, 中西徹, 滝川正春

    生化学   73 ( 8 )   710 - 710   2001

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  • Characterization of a mouse ctgf 3 '-UTR segment that mediates repressive regulation of gene expression Reviewed

    S Kondo, S Kubota, T Eguchi, T Hattori, T Nakanishi, T Sugahara, M Takigawa

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   278 ( 1 )   119 - 124   2000.11

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    We isolated a small segment of the 3'-untranslated region (3'-UTR) in the mouse connective tissue growth factor (ctgf/fisp12) gene and evaluated its functionality. Comparison of the nucleotide sequences of human and mouse ctgf 3'-UTRs revealed a conserved small segment of 91 bases, The corresponding segments of the 3'-UTRs shared as much as 82.4% homology, whereas the overall homology between the 3'-UTRS was 71.8%. To study the functionality of the conserved segment, the corresponding region of mouse ctgf cDNA was amplified from NIH3T3 cells. When it was fused downstream of a marker gene, it showed remarkable repressive effects on gene expression. The repressive effect of the sense form was more prominent than that of the antisense form. Computer analyses of these sequence predicted stable secondary structures, suggesting that they act at the RNA level. The predicted structures of the sense and antisense forms appeared to be slightly different, which is consistent with the difference in repressive function. These findings defined the conserved small element in the mouse ctgf gene as a potent negative regulator of gene expression, which may act at a posttranscriptional level. (C) 2000 Academic Press.

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  • Identification of an RNA element that confers post-transcriptional repression of connective tissue growth factor/hypertrophic chondrocyte specific 24 (ctgf/hcs24) gene: Similarities to retroviral RNA-protein interactions

    S Kubota, S Kondo, T Eguchi, T Hattori, T Nakanishi, RJ Pomerantz, M Takigawa

    ONCOGENE   19 ( 41 )   4773 - 4786   2000.9

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    The repressive effect of the 3'-untranslated region (3'-UTR) in human connective tissue growth factor/hypertrophic chondrocyte specific 24 (ctgf/hcs24) mRNA on gene expression had been demonstrated in our previous study. Here, we identified a minimal RNA element in the 3'-UTR, which acts as a cis-acting element of structure-anchored repression (CAESAR). Deletion analyses of the 3'-UTR led us to minimize the element of 84 bases at the junction of the coding region and the 3'-UTR. The minimized RNA segment is predicted, and actually capable of forming a stable secondary structure in vitro. Mutational analyses disclosed a significant relationship between the predicted structure and repressive effect. The utility of CAESAR as a post-transcriptional regulatory element was represented by the fact that steady-state mRNA levels were not affected by CAESAR linked in cis, while protein levels from such a chimeric gene were markedly reduced. Of note, the CAESAR sequence exerted no effect, when it was placed upstream of the promoter. Finally, RNA gel electromobility-shift analyses demonstrated a nuclear factor that interacts with the folded CAESAR. Taken together, it was uncovered that CAESAR of ctgf is a novel post-transcriptional structured RNA regulatory element, probably acting through direct interactions with a nuclear factor as observed in retroviral RNA elements with certain proteins.

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  • Molecular cloning and characterization of RA-A47, a rheumatoid arthritis-related antigen from a human chondrocytic cell line, HCS-2/8.

    T Hattori, S Kubota, Y Yutani, T Fujisawa, T Nakanishi, M Takigawa

    JOURNAL OF BONE AND MINERAL RESEARCH   15   S470 - S470   2000.9

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  • A novel RNA element that confers post-transcriptional repression of human connective tissue growth factor/hypertrophic chondrocyte specific 24 (ctgf/hcs24) gene.

    S Kubota, S Kondo, T Eguchi, T Hattori, T Nakanishi, RJ Pomerantz, M Takigawa

    JOURNAL OF BONE AND MINERAL RESEARCH   15   S340 - S340   2000.9

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  • Novel intracellular effects of human connective tissue growth factor expressed in Cos-7 cells Reviewed

    S Kubota, T Hattori, T Shimo, T Nakanishi, M Takigawa

    FEBS LETTERS   474 ( 1 )   58 - 62   2000.5

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    To clarify the multiple functionality of connective tissue growth factor (CTGF), we examined the effects of nascent CTGF within the cell by transient expression. Tn Cos-7 cells, expression of human CTGF induced an altered cell morphology, It was associated with an increased cellular DNA content and loose attachment, indicating the cells mere in G2/M phase. Overexpression of CTGF did not induce cell growth, whereas recombinant CTGF efficiently stimulated the proliferation extracellularly, These results indicate that intracellular CTGF may act as an antimitotic agent, thus it should also be noted that nascent CTGF was found to accumulate around the central mitotic machinery. (C) 2000 Federation of European Biochemical Societies.

    DOI: 10.1016/S0014-5793(00)01573-8

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  • 結合組織成長因子/肥大軟骨細胞特異的遺伝子産物(CTGF/Hcs24)発現による細胞周期変調効果

    久保田 聡, 服部 高子, 志茂 剛, 中西 徹, 滝川 正春

    Connective Tissue   32 ( 2 )   217 - 217   2000.5

  • マトリクラインとMMP

    服部高子, 滝川正春

    現代医療   32(4), 909-915 ( 4 )   909 - 915   2000

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  • Downregulation of a rheumatoid arthritis-related antigen (RA-A47) by stimulation of inflammatory cytokines in chondrocytic cell line, HCS-2/8.

    Hattori, T

    J. Okayama Dent. Soc.   19 ( 2 )   241 - 254   2000

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  • Study on rheumatoid arthritis-related antigen (RA-A47) isolated from chondrocytes.

    Hattori, T

    Dissertation   2000

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  • 慢性関節リウマチ関連抗原RA-A47の発現量減少による軟骨細胞障害作用

    服部高子, 川木晴美, 油谷安孝, 久保田聡, 中西徹, 滝川正春

    生化学   72 ( 8 )   922 - 922   2000

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  • 軟骨由来成長因子CTGF/Hcs24遺伝子の転写後調節エレメントCAESAR 変異体分析によって得られた新たな知見

    久保田聡, 近藤誠二, 江口傑徳, 服部高子, 中西徹, 滝川正春

    日本分子生物学会年会プログラム・講演要旨集   23rd   2000

  • ヒト軟骨細胞様培養細胞株HCS-2/8における結合組織成長因子ctgf/ecogenin遺伝子発現制御機構

    江口傑徳, 久保田聡, 近藤誠二, 服部高子, 中西徹, 窪木拓男, 矢谷博文, 滝川正春

    日本分子生物学会年会プログラム・講演要旨集   23rd   2000

  • 軟骨由来の成長因子CTGF/Hcs24遺伝子に同定された新たな転写後制御エレメント,CAESAR

    久保田聡, 近藤誠二, 江口傑徳, 服部高子, 中西徹, 滝川正春

    日本骨代謝学会雑誌   18 ( 2 )   119 - 119   2000

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  • 軟骨細胞および線維芽細胞株におけるCTGF/Ecogenin遺伝子発現の3′-UTRによる調節

    近藤誠二, 久保田聡, 江口傑徳, 服部高子, 中西徹, 菅原利夫, 滝川正春

    岡山歯学会雑誌   19 ( 1 )   205 - 206   2000

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  • 慢性関節リウマチ関連抗原RA-A47の発現量減少による軟骨細胞破壊とアポトーシスの誘導

    服部高子, 久保田聡, 中西徹, 油谷安孝, 滝川正春

    日本分子生物学会年会プログラム・講演要旨集   23rd   2000

  • 軟骨細胞の基質代謝におよぼす周期的メカニカルストレスの影響

    藤沢拓生, 服部高子, 窪木拓男, 矢谷博文, 山下敦, 滝川正春

    日本顎関節学会雑誌   12 ( 1 )   133 - 134   2000

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  • 軟骨由来成長因子CTGF/Hcs24による軟骨分化マーカーII型コラーゲンおよびX型コラーゲンの発現促進に対するMAPキナーゼ経路阻害剤の効果

    吉道玄, 中西徹, 服部高子, 西田崇, 山本照子, 滝川正春

    日本骨代謝学会雑誌   18 ( 2 )   2 - 2   2000

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  • 慢性関節リウマチ関連抗原RA-A47の発現レベルの低下にともなう細胞膜への局在変化とRA-A47の自己抗原としての認識機構

    服部高子, 油谷安孝, 藤沢拓生, 中西徹, 滝川正春

    日本骨代謝学会雑誌   18 ( 2 )   148 - 148   2000

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  • 軟骨由来成長因子CTGFと転写制御因子Cbfa1の発生過程での遺伝子発現のパターン解析

    山合友一郎, 中西徹, 浅野将宏, 縄稚久美子, 服部高子, 杉本朋貞, 滝川正春

    歯科基礎医学会雑誌   42 ( 5 )   451 - 451   2000

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  • 軟骨由来の成長因子CTGF/Hcs24遺伝子の転写後制御エレメント,CAESARの構造機能連関

    久保田聡, 近藤誠二, 江口傑徳, 服部高子, 中西徹, 滝川正春

    生化学   72 ( 8 )   972 - 972   2000

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  • 軟骨由来の慢性関節リウマチ関連抗原RA-A47に関する研究。

    岡山大学 学位論文   2000

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  • A cis-acting repressive element in the 3 '-untranslated region of the CTGF gene.

    S Kubota, T Hattori, T Eguchi, S Kondo, T Nakanishi, M Takigawa

    JOURNAL OF BONE AND MINERAL RESEARCH   14   S436 - S436   1999.9

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  • 軟骨由来成長因子CTGF/Hcs24のマウス発生過程での遺伝子発現のパターン解析

    山合 友一朗, 浅野 将宏, 中西 徹, 西田 崇, 吉道 玄, 服部 高子, 杉本 朋貞, 滝川 正春

    歯科基礎医学会雑誌   41 ( 5 )   464 - 464   1999.8

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  • 慢性関節リウマチにおけるRA-A47の細胞内局在変化と抗原提示

    服部 高子, 藤沢 拓生, 中西 徹, 久保田 聡, 滝川 正春

    歯科基礎医学会雑誌   41 ( 5 )   431 - 431   1999.8

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  • 軟骨由来の成長因子CTGF/Hcs24の細胞内での動態と機能

    久保田 聡, 服部 高子, 志茂 剛, 中西 徹, 滝川 正春

    生化学   71 ( 8 )   892 - 892   1999.8

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  • TNFαによるRA-A47の軟骨細胞内局在の変化と抗原提示

    服部 高子, 藤沢 拓生, 油谷 安孝, 中西 徹, 滝川 正春

    生化学   71 ( 8 )   969 - 969   1999.8

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  • 軟骨由来の成長因子 Hcs24/CTGF(Ecogenin) の遺伝子発現調節メカニズム

    久保田 聡, 服部 高子, 中西 徹, 滝川 正春

    日本骨代謝学会雑誌 = Japanese journal of bone metabolism   17 ( 2 )   81 - 81   1999.6

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  • 軟骨由来成長因子Hcs24/CTGFのマウス胎生期における発現とCbfa1による制御

    中西 徹, 浅野 将宏, 山合 友一朗, 小守 寿文, 西田 崇, 吉道 玄, 服部 高子, 滝川 正春

    日本骨代謝学会雑誌 = Japanese journal of bone metabolism   17 ( 2 )   5 - 5   1999.6

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  • Repressive Effect of the 3′-Untranslated Region in the Human Connective Tissue Growth Factor(CTGF)cDNA on Gene Expression.

    Kubota Satoshi, Hattori Takako, Nakanishi Tohru, Takigawa Masaharu

    Connective tissue   31 ( 2 )   125 - 125   1999.6

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  • 周期的な機械的ストレスを培養軟骨細胞に加え続けると,MMP及びIL-1の発現が誘導され,細胞外マトリックスの分解が引き起こされる

    Fujisawa Takuo, Hattori Takako, Takahashi Kojiro, Kuboki Takuo, Yamashita Atsushi, Takigawa Masaharu

    The Journal of Biochemistry   125 ( 5 )   966 - 975   1999.5

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    機械的刺激による軟骨の分解について調べた.Flexercell strain unitを用いて周期的張力(CTF)を培養軟骨細胞に加えたところ,5kPa及び15kPaの高頻度CTFにより,DNA合成,プロテオグリカン合成,コラーゲン合成の低下が見られた.15kPaの高頻度CTFではIL-1,matrix metalloproteinase-2(MMP-2),MMP-9のmRNAの発現と活性型MMP-9の産生が増加した.この時,プロテオグリカンの分解が促進したが,MMPの阻害剤の存在下では分解の促進が抑えられた.張力を小さくすると,軟骨の分解に関わる遺伝子の発現誘導は見られなかった.強度の高頻度CTFはIL-1,MMP-2,MMP-9のmRNAの発現,及び活性型MMP-9の産生を増大させることから,周期的な機械的ストレスが軟骨の分解を引き起こすと考えられる

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  • Involvement of cis-acting repressive element(s) in the 3''-untranslated region of human connective tissue growth factor gene. Reviewed

    S Kubota, T Hattori, T Nakanishi, M Takigawa

    FEBS Letters   450 ( 1-2 )   84 - 88   1999.4

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    To analyze the regulatory mechanism of connective tissue growth factor expression, the 3'-untranslated region (3'-UTR) of CTGF cDNA was amplified from HeLa cell RNA. Direct nucleotide sequencing revealed a single major population in the amplicon, which was nearly identical to other sequences. Subsequently, the effect of the 3'-UTR on gene expression was evaluated. When it,vas fused downstream of a firefly luciferase gene, the 3'-UTR strongly repressed luciferase gene expression. Interestingly, the repressive effect of the antisense 3'-UTR appeared to be more prominent than that of the sense one. Together with the fact that several consensus sequences for regulatory elements are found in it, these results suggest the involvement of multiple sets of regulatory elements in the CTGF 3'-UTR, (C) 1999 Federation of European Biochemical Societies.

    DOI: 10.1016/S0014-5793(99)00480-9

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  • 慢性関節リウマチ関連抗原RA-A47は自己の発現レベルの低下にともない細胞膜へと局在が変化する

    服部高子, 油谷安孝, 藤沢拓生, 中西徹, 滝川正春

    日本分子生物学会年会プログラム・講演要旨集   22nd   1999

  • 慢性関節リウマチ患者血清が認識するHSP47様抗原蛋白(RA-A47)のヒト軟骨細胞様細胞株からの同定と同抗原蛋白の生理的・病理的意義

    平成9年度財団法人両備てい園記念財団研究助成金による研究報告-生物学に関する試験研究論叢   14   108 - 115   1999

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  • 軟骨由来成長因子Hcs24/CTGF組換え蛋白質の軟骨細胞及び血管内皮細胞に対する増殖・分化促進作用

    浅野 将宏, 中西 徹, 志茂 剛, 西田 崇, 服部 高子, 滝川 正春

    歯科基礎医学会雑誌   40 ( 抄録 )   389 - 389   1998.9

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  • 軟骨由来成長因子Hcs24/CTGF受容体の同定と軟骨細胞の分化による受容体数の変動

    西田 崇, 中西 徹, 志茂 剛, 浅野 将宏, 服部 高子, 滝川 正春

    歯科基礎医学会雑誌   40 ( 抄録 )   389 - 389   1998.9

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  • 軟骨由来成長因子Hcs24/CTGF組換え蛋白質の内軟骨性骨化促進作用

    中西 徹, 志茂 剛, 西田 崇, 浅野 将宏, 服部 高子, 玉谷 卓也, 手塚 克成, 滝川 正春

    生化学   70 ( 8 )   975 - 975   1998.8

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  • 細胞膜受容体 軟骨由来成長因子Hcs24/CTGF受容体の同定と軟骨細胞の分化に伴う変動

    西田 崇, 中西 徹, 志茂 剛, 浅野 将宏, 服部 高子, 玉谷 卓也, 手塚 克成, 滝川 正春

    生化学   70 ( 8 )   805 - 805   1998.8

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  • 慢性関節リウマチ関連抗原蛋白RA-A47 cDNAの単離と構造解析

    服部 高子, 油谷 安孝, 藤沢 拓生, 中西 徹, 高橋 浩二郎, 滝川 正春

    生化学   70 ( 8 )   848 - 848   1998.8

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  • 慢性関節リウマチ関連抗原蛋白RA-A47 cDNAの単離と抗原提示機構

    服部 高子, 油谷 安孝, 佐々木 和浩, 藤沢 拓生, 中西 徹, 高橋 浩二郎, 滝川 正春

    日本骨代謝学会雑誌 = Japanese journal of bone metabolism   16 ( 2 )   4 - 4   1998.7

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  • 軟骨由来成長因子Hcs24/CTGFの組換え蛋白質は軟骨細胞と血管内皮細胞に働いて内軟骨性骨化を促進する

    中西 徹, 志茂 剛, 西田 崇, 浅野 将宏, 服部 高子, 玉谷 卓也, 手塚 克成, 滝川 正春

    日本骨代謝学会雑誌 = Japanese journal of bone metabolism   16 ( 2 )   28 - 28   1998.7

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  • 軟骨由来成長因子Hcs24/CTGFの特異的受容体の同定と内軟骨性骨化における意義

    西田 崇, 中西 徹, 志茂 剛, 浅野 将宏, 服部 高子, 玉谷 卓也, 手塚 克成, 滝川 正春

    日本骨代謝学会雑誌 = Japanese journal of bone metabolism   16 ( 2 )   27 - 27   1998.7

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  • 軟骨細胞の基質合成におけるメカニカルストレスの影響

    藤沢 拓生, 服部 高子, 佐々木 和浩, 高橋 浩二郎, 滝川 正春

    日本骨代謝学会雑誌 = Japanese journal of bone metabolism   16 ( 2 )   109 - 109   1998.7

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  • Induction of in vitro angiogenesis by recombinant chondrocyte-derived growth factor Hcs24 / CTGF

    Shimo T., Nakanishi T., Nishida T., Asano M., Hattori T., Matsumura T., Takigawa M.

    Connective tissue   30 ( 2 )   153 - 153   1998.6

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  • 培養ラビット関節軟骨細胞において,インターロイキン1により誘導されるマトリックスメタロプロテイナーゼや塩基性線維芽細胞成長因子の遺伝子発現はNOを介して行われる

    Sasaki Kazuhiro, Hattori Takako, Fujisawa Takuo

    The Journal of Biochemistry   123 ( 3 )   431 - 439   1998.3

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    著者等は近年,IL-1処理により産生したNOにより関節軟骨細胞マトリックスに蓄積されていたbFGFが放出されることを報告した.今回はこのメカニズムを解明するためラビット関節軟骨細胞をIL-1処理したときのbFGF,MMPs(matrix metalloproteinases),syndecan3,iNOS(inducible NO synthase)の産生量を調べた.その結果,IL-1処理によりこれら全ての産生量は増大し,MMPsではMMP-3,MMP-9が増加した.また,MMP inhibitorによりbFGFの放出量が一部減少したことからbFGFの放出にはマトリックスが関与していることが示唆された.またIL-1はiNOS,menbrane type 1-MMP,MMP-9,MMP-3 bFGFの順にmRNAの発現を刺激した.また,NOの産生抑制により,MMP-9,bFGFの遺伝子発現は抑制された.以上より,IL-1刺激によるNOの産生を介して,MMPsやbFGFの産生が起こることが明らかとなり,更に関節接合部の滑膜における軟骨分解後の血管再生の分子メカニズムが示唆された

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  • Effect of cyclic mechanical stress on chondrocyte metabolism.

    T Fujisawa, T Hattori, T Kuboki, A Yamashita, M Takigawa

    JOURNAL OF DENTAL RESEARCH   77   1004 - 1004   1998

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  • Cloning and characterization of ra-a47 gene which encodes 47 kDa of rheumatoid arthritis-related antigen (RA-A47) protein

    HATTORI Takako, YUTANI Yasutaka, FUJISAWA Takuo, NAKANISHI Tohru, TAKIGAWA Masaharu

    21st   461   1998

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  • VEGF.

    服部高子, 滝川正春

    関節外科   17 ( 7 )   904 - 905   1998

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  • HSP47様慢性関節リウマチ関連抗原(RA-A47)の単離と機能解析

    服部 高子

    岡山歯学会雑誌   16 ( 2 )   240 - 240   1997.12

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  • Expression and heterozygosity of imprinting IGF-II and H19 in the human chondrosarcoma-derived cells. HCS-2/8 and -2/A

    K Takahashi, TH Vu, T Hattori, T Nakanishi, AR Hoffman, M Takigawa

    FASEB JOURNAL   11 ( 9 )   A937 - A937   1997.7

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    Overexpression of insulin-like growth facloi-II gene (IGF2) in Wilms' tumor occurs through a process independent on the loss of heterogosity or loss of imprinting (W.U. Wang el al. : J. Biol. Them. 271,27X63, 1996) In the human chondrosarcoma-denved HCS-2/8 and -2/A cell lines, cloned by M Takigawa et al. (Cancel Res. 49 39%, 1989;Int J. Cancel 48. 717, 1991), total expression from 4 promoters (PI, P2, P3, P4) of 1GF2 and expression of H19 were 4-ft times and 1-0.5 times, respectively, compared to human normal chondrocytcs. In order to probe the mechanism of IGF2 Overexpression and repressive H19 expression in HCS-2/8 and -2/A cells, the imprinting and hetcro/ygosity ot 1GF2 and H19 were examined by restriction fragment length poly moi phi suis (RFLP) and sequence analyses with their RT-PCR products. RT-PCR products from all promoters and genomic PCR product of 1GF2 in HCS-2/8 were perfectly digested at Apal site on Exon9 (Ex9), suggesting the paternal allelc expression. However, the RT-PCR product from PI was partially cut at Alu\ site on the 5'-region of Ex3, of which the sequence data indicated both alleles expression. In RT-PCR product from P4, lacking of 4 bases in Ace I site at joint portion between Ex6-E.x7 occured bv the alternative splicing. While, RT-PCR product of the 5′-rcgion of E.x5 on H19 in HCS-2/K was not digested by Rsa] at all, suggesting the maternal allelc expression. Sequence data of the RT-PCR product suggested the existence of other RF''LP sites (MscI, DdeI, BsgI,) besides Alu\ and Rsal sites. These results imply that IGF2 Overexpression and repressive H19 expression may not relate directly with the imprinting status of IGF2 and HI9 in the chodrosarccma cells.

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  • Function of a HSP47-Like Rheumatoid Arthritis-Related Antigen(RA-A47).

    服部高子, 油谷安孝, 佐々木和浩, 藤沢拓生, 中西徹, 高橋浩二郎, 滝川正春

    日本分子生物学会年会プログラム・講演要旨集   20th ( 7 )   903 - 903   1997

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  • Identification of Protein Tyrosine Phosphatase Related to the Cell Density-Dependent Growth Inhibition of Murine Osteoblastic cells.

    高橋浩二郎, 森川雅之, 服部高子, 中西徹, 滝川正春

    日本分子生物学会年会プログラム・講演要旨集   20th   1997

  • Roles of cartilage-derived multifunctional growth factor CTGF/Hcs24 in intracartilaginous bone formation. Expression and action mechanisms in the cartilage, blood vessel and nerves.

    中西徹, 遠藤剛, 西田崇, 服部高子, 竹林俊明, 松村智弘, 石関清人, 滝川正春

    日本骨代謝学会雑誌   15 ( 2 )   23   1997

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  • Connective Tissue Growth Factor Mediates TGF-β-stimulated DNA Synthesis in a Human Chondrocytic Cell Line Acting Through Its Specific Receptors.

    西田崇, 中西徹, 志茂剛, 服部高子, 浅野将宏, 玉谷卓也, 手塚克成, 滝川正春

    日本分子生物学会年会プログラム・講演要旨集   20th   1997

  • Cartilage-derived chronic articular rheumatism-related antigen protein RA-A47. Differences with HSP47 and suppression of expression by inflammatory cytokines.

    服部高子, 油谷安孝, 佐々木和浩, 藤沢拓生, 中西徹, 高橋浩二郎, 滝川正春

    日本骨代謝学会雑誌   15 ( 2 )   226 - 226   1997

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  • Relation between cartilage destruction and neovascularization in arthritis : IL-1 accelerates not only liberation of bFGF from cultured cartilage cells but also the production and the gene expression.

    佐々木和浩, 服部高子, 藤沢拓生, 中西徹, 高橋浩二郎, 井上一, 滝川正春

    日本骨代謝学会雑誌   15 ( 2 )   225   1997

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  • ヒト関節軟骨細胞様細胞株の樹立と慢性関節リウマチへの応用-コラーゲン特異的分子シャペロンHSP47様蛋白質の単離とリウマチ関連抗原としての意義-

    平成9年度長期慢性疾患総合研究事業リウマチ班総合班会議プログラム   18 - 19   1997

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  • Specific serum antibodies against membranous proteins of a human immortal chondrocytic cell line (HCS-2/8) in rheumatoid arthritis and their relationship to the natural history of this disease

    Akira Sakawa, Yasutaka Yutani, Kentaro Inui, Akira Shimazu, Yoshiki Yamano, Akira Kinosita, Fujio Suzuki, Takako Hattori, Masaharu Takigawa

    Journal of Bone and Mineral Metabolism   14 ( 3 )   146 - 152   1996.9

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    An immortal human chondrocytic cell line (HCS-2/8) derived from a chondrosarcoma was used as a source of human antigens to find humoral antibodies to cell surface proteins of human chondrocytes in sera from patients with rheumatoid arthritis (RA). Membrane fractions prepared from the cell line were subjected to Western blot analysis using RA and normal sera as probes. RA sera recognized about a dozen bands, but three of these bands, with molecular weights of 105 kDa, 68 kDa, and 47 kDa, were found to be specific for the RA sera (P &lt
    0.05). These bands disappeared following V8 protease digestion, indicating that they were proteins. Among patients with 4 years or more of RA disease activity, reactivity against 105-kDa and 68-kDa proteins was relatively high in those whose joints showed a high degree of erosion. We suspect that levels of these two antibodies are suggestive of changes associated with the natural course of RA.

    DOI: 10.1007/BF02239482

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  • 慢性関節リウマチ関連抗原蛋白RA-A47の構造と生理的・病理的意義

    服部 高子

    歯科基礎医学会雑誌   38 ( 抄録 )   461 - 461   1996.8

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  • Property and structure of rheumatoid arthritis relevant antigen protein (RA-A47).

    服部高子, 佐々木和浩, 油谷安孝, 木村祐輔, 中西徹, 高橋浩二郎, 永田和宏, 滝川正春

    日本分子生物学会年会プログラム・講演要旨集   68 ( 7 )   691 - 691   1996.7

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  • 軟骨特異的CTGF関連遺伝子hcs24の単離とその機能解析

    中西 徹, 木村 祐輔, 田村 知雄, 遠藤 剛, 西田 崇, 村上 崇子, 服部 高子, 滝川 正春

    日本骨代謝学会雑誌 = Japanese journal of bone metabolism   14 ( 2 )   51 - 51   1996.6

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  • ヒト軟骨細胞様細胞株(HCS-2/8)由来の慢性関節リウマチ関連抗原RA-A47 : その構造と性状

    服部 高子, 油谷 安孝, 佐々木 和浩, 中西 徹, 高橋 浩二郎, 滝川 正春

    日本骨代謝学会雑誌 = Japanese journal of bone metabolism   14 ( 2 )   71 - 71   1996.6

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  • ヒト軟骨肉腫由来軟骨細胞様培養細胞株HCS-2/8におけるigf-II遺伝子プロモータの発現変動に対するアスコルビン酸の影響

    高橋 浩二郎, 服部 高子, 木村 祐輔, 中西 徹, 滝川 正春

    日本骨代謝学会雑誌 = Japanese journal of bone metabolism   14 ( 2 )   173 - 173   1996.6

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  • ヒト軟骨肉腫由来の軟骨細胞様培養細胞株でのIGF-II遺伝子の転写制御因子遺伝子の発現変動

    高橋浩二郎, 服部高子, 木村祐輔, 中西徹, 滝川正春

    日本分子生物学会年会プログラム・講演要旨集   19th   796   1996

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  • IL-1 Induces Release of Chondrocyte-associated b-FGF and Production of b-FGF by Chondrocytes.

    佐々木和浩, 服部高子, 田村知雄, 遠藤剛, 西田崇, 木村祐輔, 中西徹, 高橋浩二郎, 滝川正春

    日本整形外科学会雑誌   70 ( 8 )   S1194   1996

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  • A action in arterialization of cartilage cell growth factor Hcs24/CTGF.

    遠藤剛, 中西徹, 木村祐輔, 服部高子, 西田崇, 村上崇子, 滝川正春

    日本分子生物学会年会プログラム・講演要旨集   19th   171   1996

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  • Action mechanism for cell line (HCS-2/8) that is the human cartilage cell of cartilage cell growth factor Hcs24/CTGF.

    西田崇, 中西徹, 木村祐輔, 遠藤剛, 服部高子, 高橋浩二郎, 滝川正春

    日本分子生物学会年会プログラム・講演要旨集   19th   171   1996

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  • Property and structure of rheumatoid arthritis relevant antigen protein (RA-A47).

    服部高子, 佐々木和浩, 油谷安孝, 木村祐輔, 中西徹, 高橋浩二郎, 永田和宏, 滝川正春

    日本分子生物学会年会プログラム・講演要旨集   19th   179   1996

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  • Nitric oxide mediates interleukin-1-induced matrix degradation and basic fibroblast growth factor release in cultured rabbit articular chondrocytes. A possible mechanism of pathological neovascularization in arthritis

    Tamura, T, Nakanishi, T, Kimura, Y, Hattori, T, Sasaki, K, Norimatsu, H, Takahashi, K, Takigawa, M

    Endocrinology   137 ( 9 )   3729 - 3737   1996

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  • ヒト軟骨培養細胞様細胞株(HCS-2/8)を用いた慢性関節リウマチ特異抗原蛋白の単離とその構造決定

    服部 高子

    歯科基礎医学会雑誌   37 ( 抄録 )   140 - 140   1995.8

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  • FURTHER CHARACTERIZATION OF A HUMAN CHONDROSARCOMA-DERIVED CHONDROCYTIC CELL LINE: HCS-2/8

    TAKIGAWA Masaharu, TAKAHASHI Kojiro, NAKANISHI Tohru, HATTORI Takako, KIMURA Yusuke, PAN Hai-Ou, KINOSHITA Akihiro, NAKAJIMA Kaoru, SUZUKI Fujio, NOMURA Shintaro, OKAWA Tokutaro, ZHU Jing-de

    13 ( 1 )   40 - 40   1995

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  • Transcriptional regulation of igf-II gene in a human chondrosarcoma cell line HCS-2/8: Alteration of the expressed promoters by ascorbic acid.

    高橋浩二郎, 服部高子, 木村祐輔, 松尾智江, 坪井佳子, 田村知雄, 中西徹, 井上一, 滝川正春

    日本分子生物学会年会プログラム・講演要旨集   18th   1995

  • Characterization of a rheumatoid arthritis-related antigen purified from a human chondrocytic cell line.

    服部高子, 田村知雄, 佐々木和浩, 木村祐輔, 油谷安孝, 中西徹, 高橋浩二郎, 滝川正春

    日本分子生物学会年会プログラム・講演要旨集   18th   1995

  • Cloning of cartilage specific gene by Differential Display.

    中西徹, 木村祐輔, 田村知雄, 村上崇子, 服部高子, 高橋浩二郎, 滝川正春

    日本骨代謝学会雑誌   13 ( 2 )   1995

  • Overexpression and expression promoter fluctuation and genome imprinting of IGF-II gene in cultured cartilage cells (HCS-2/8) derivated from human chondrosarcoma.

    高橋浩二郎, 木村祐輔, 服部高子, 中西徹, 田村知雄, 滝川正春

    日本骨代謝学会雑誌   13 ( 2 )   307 - 307   1995

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  • Vascularization factor is liberated from cartilage cell by interleukin - 1(IL1) through NO production.

    田村知雄, 中西徹, 木村祐輔, 服部高子, 村上崇子, 乗松尋道, 高橋浩二郎, 滝川正春

    日本骨代謝学会雑誌   13 ( 2 )   59   1995

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  • Isolation of a CTGF-related gene from chondrocytes and analysis of its function.

    中西徹, 木村祐輔, 田村知雄, 遠藤剛, 西田崇, 村上崇子, 服部高子, 高橋浩二郎, 滝川正春

    日本分子生物学会年会プログラム・講演要旨集   18th ( 2 )   252   1995

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  • 大腸菌narオペロンの転写調節因子NarXおよびNarLの調製とその機能

    服部 高子

    生化学   66 ( 7 )   780 - 780   1994.7

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  • DIFFERENTIAL EXPRESSION OF HOMEOBOX-CONTAINING GENES MSX-1 AND MSX-2 AND HOMEOPROTEIN MSX-2 EXPRESSION DURING CHICK CRANIOFACIAL DEVELOPMENT

    K NISHIKAWA, T NAKANISHI, C AOKI, T HATTORI, K TAKAHASHI, S TANIGUCHI

    BIOCHEMISTRY AND MOLECULAR BIOLOGY INTERNATIONAL   32 ( 4 )   763 - 771   1994.3

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    The expression pattern of chick Msx-1 and Msx-2 homeobox genes in craniofacial primordia was examined by in situ hybridization using cRNA probes. Both genes were expressed in the distal region of the facial primordia, where the distribution of Msx-2 expression was restricted distally within the Msx-1 expression domain. On the contrary, Msx-2 expression in the lateral choroid plexus and cranial skull was broader and more intensive than Msx-1 expression. Our findings suggest that these two genes cooperate to play differential roles in craniofacial development. Msx-2 protein was detected immunohistochemically, and its localization essentially corresponded to the mRNA expression pattern, substantiating the involvement of Msx-2 protein as a transcriptional regulator in developing limb and face.

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  • Phosphorylation of purified NarL protein and interactions among NarL, FNR and IHF on E. coli nar operon.

    服部高子, 高橋浩二郎, 中西徹, 神藤平三郎, 谷口茂彦, 滝川正春

    日本分子生物学会年会プログラム・講演要旨集   17th   1994

  • 口腔内通性嫌気性細菌における分子状酸素センサー兼転写調節因子FNR様タンパクおよびその構造遺伝子の比較解析

    服部高子, 高橋浩二郎, 太田寛行, 谷口茂彦

    乳酸菌研究会に関する報告書   1994

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  • Expression of trk C in a mouse osteoblastic cell line and its response to neurotrophine-3.

    Nakanishi, T., Ohyama, K., Aoki, C., Kudo, A., Hattori, T., Takahashi, K., Taniguchi, S., Takigawa, M.

    Biochem. Biophys. Res. Commun.   23 ( 2 )   1268 - 1274   1994

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  • Differential expression of homeobox - containing genes Msx-1 and Msx-2 and homeo protein Msx-2 expression during chick craniofacial development.

    Nishikawa, K, Nakanishi, T, Aoki, C, Hattori, T, Takahashi, K, Taniguchi, S

    Biochem. Mol. Biol. Inter.   32 ( 4 )   763 - 771   1994

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  • Expression of trkC in a mouse osteoblastic cell line and its response to neurotrophin-3.

    中西徹, 木村祐輔, 村上崇子, 大山和美, 岩田恵美, 小川紀雄, 服部高子, 高橋浩二郎, 滝川正春

    日本分子生物学会年会プログラム・講演要旨集   17th   1994

  • Actinobacillus actinomycetemcomitansにおけるFNR様蛋白と嫌気的呼吸系

    服部 高子

    歯科基礎医学会雑誌   35 ( 抄録 )   195 - 195   1993.9

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  • msh型ホメオボックス遺伝子の融合ペプチド発現系の構築と抗体作製

    西川清, 中西徹, 青木千春, 服部高子, 高橋浩二郎, 谷口茂彦

    日本分子生物学会年会プログラム・講演要旨集   16th   1993

  • マウス骨芽細胞株における神経成長因子ファミリー遺伝子の発現とその構造解析

    中西徹, 青木千春, 高橋浩二郎, 西川清, 服部高子, 谷口茂彦

    日本分子生物学会年会プログラム・講演要旨集   16th   1993

  • 通性嫌気性口腔内細菌Actinobacillus actinomycetemcomitansにおける分子状酸素センサー兼転写調節因子FNRタンパクの単離精製と、硝酸塩添加時の嫌気的増殖

    服部高子, 高橋浩二郎, 太田寛行, 谷口茂彦

    乳酸菌研究会に関する報告書   ,430-438   1993

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  • Actinobacillus actinomycetemcomitansにおける嫌気的呼吸系制御蛋白質 FNR

    服部 高子

    歯科基礎医学会雑誌   34 ( 抄録 )   152 - 152   1992.9

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  • 大腸菌の嫌気呼吸系遺伝子群の転写抑制蛋白質 FNRによるfnr遺伝子の自己抑制

    服部 高子

    生化学   64 ( 7 )   585 - 585   1992.7

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  • 大腸菌嫌気的呼吸系転写制御蛋白質: FNRの抑制的転写制御

    高橋浩二郎, 服部高子, 中西徹, 野地澄晴, 濃野勉, 斎藤泰一, 藤田信之, 石浜明, 谷口茂彦

    日本生物物理学会年会講演予稿集   30th   1992

  • 嫌気的呼吸系遺伝子群の発現制御にあずかるFNR様転写調節タンパクの口腔細菌における分布と動態、乳酸菌研究会に関する報告書

    高橋浩二郎, 服部高子, 太田寛行, 野地澄晴, 谷口茂彦

    396-403   1992

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Presentations

  • 軟⾻組織においてCCN3の発現上昇は、年齢、荷重の有無に関わらず軟⾻ 変性度と相関する

    桑原 実穂, 廣瀬 一樹, 奥田 龍一郎, Janvier Habumugisha, 近藤 星, Shanqi Fu, 大野 充昭, 古松毅之, 中田 英二, 滝川 正春, 久保田 聡, 服部 高子

    第46回日本分子生物学会年会  2023.12.6 

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    Event date: 2023.12.6 - 2023.12.8

    Presentation type:Symposium, workshop panel (public)  

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  • 軟骨組織の加齢とともに発現が上昇するCCN3は、その発現上昇と軟骨変性度が年齢、荷重の有無に関わらず相関する

    桑原 実穂, 廣瀬 一樹, 近藤 星, Fu Shanqi, 大野 充昭, 古松 毅之, 中田 英二, 滝川 正春, 久保田 聡, 服部 高子

    第96回日本生化学会大会  2023.10.31 

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    Event date: 2023.10.31 - 2023.11.2

    Presentation type:Poster presentation  

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  • CCN3は軟骨細胞老化マーカーであり、年齢、荷重の有無に関わらず変形性関節症と相関する

    服部 高子, 滝川 正春, 久保田 聡

    第65回歯科基礎医学会学術大会  2023.9.18 

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    Event date: 2023.9.16 - 2023.9.18

    Presentation type:Oral presentation (general)  

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  • 軟骨組織におけるCCN3の老化マーカーとしての役割と、CCN3の異所性発現による加齢様退行性変化の促進

    桑原 実穂, 廣瀬 一樹, 近藤 星, 古松 毅之, 中田 英二, 原 哲也, 久保田 聡, 服部 高子

    日本結合組織学会学術大会プログラム・抄録集  2023.6  日本結合組織学会

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    Event date: 2023.6

    Language:Japanese  

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  • 軟骨細胞におけるメトホルミンによるlong non-coding RNA, UCA1およびCCN2の発現制御

    近藤 星, 服部高子, 桑原実穂, Fu Shanqi, 西田 崇, 薬師寺翔太, 吉岡洋祐, 森谷徳文, 飯田征二, 滝川正春, 久保田聡

    第45回日本分子生物学会 日本生物物理学会 共催  2022.12.2 

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    Event date: 2022.11.30 - 2022.12.2

    Presentation type:Oral presentation (general)  

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  • 軟骨組織の加齢変性におけるCCN3の機能

    桑原実穂, 近藤 星, Fu Shanqi, 大野充昭, 古松毅之, 中田英二, 滝川正春, 服部高子, 久保田聡

    第95回日本生化学会  2022.11.9 

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    Event date: 2022.11.9 - 2022.11.11

    Presentation type:Oral presentation (general)  

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  • 軟骨細胞におけるメトホルミンによるlong non-coding RNA, UCA1およびCCN2の発現制御

    近藤 星, 服部高子, 桑原実穂, Fu Shanqi, 西田 崇, 薬師寺翔太, 吉岡洋祐, 森谷徳文, 飯田征二, 滝川正春, 久保田聡

    第45回日本分子生物学会 日本生物物理学会 共催  2022.11 

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  • DO NOT OVERWORK: CCN3 FOR LIFE IN CARTILAGE

    2022.10 

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  • メトホルミンの軟骨細胞におけるlong non-coding RNA, UCA1およびCCN2の発現制御と代謝における意義

    近藤 星, 服部高子, 桑原実穂, Fu Shanqi, 西田 崇, 薬師寺翔太, 吉岡洋祐, 森谷徳文, 飯田征二, 滝川正春, 久保田聡

    第13回日本CCNファミリー研究会  2022.9.3 

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    Event date: 2022.9.3

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  • CCN3の関節軟骨における発現は、年齢、荷重の有無に関わらず変形性関節症と相関する –股関節を用いた研究–

    廣瀬一樹, 服部高子, 桑原実穂, 滝川正春, 久保田聡

    第13回日本CCNファミリー研究会  2022.9.3 

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    Event date: 2022.9.3

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  • 変形性関節症とCCN3発現の相関

    廣瀬一樹, 服部高子, 桑原実穂, 滝川正春, 中田英二, 鉄永智紀, 山田和希, 佐藤嘉洋, 小浦 卓, 尾崎敏文, 久保田聡

    第40回日本骨代謝学会  2022.7.22 

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    Event date: 2022.7.22 - 2022.7.23

    Presentation type:Oral presentation (general)  

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  • 変形性股関節症とCCN3発現の相関

    廣瀬一樹, 服部高子, 桑原実穂, 滝川正春, 中田英二, 鉄永智紀, 山田和希, 佐藤嘉洋, 小浦 卓, 尾崎敏文, 久保田聡

    第40回日本骨代謝学会  2022.7 

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  • グルタチオンによる破骨細胞形成促進にシステイニルロイコトリエン受容体CysLTR1は関与しない

    藤田洋史, 土生田宗憲, 服部高子, 久保田聡, 大内淑代

    第75回日本酸化ストレス学会学術集会  2022.5.25 

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    Event date: 2022.5.25 - 2022.5.26

    Presentation type:Oral presentation (general)  

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  • Cysltr1変異はリポポリサッカリドによるマウス頭蓋冠の骨破壊に影響しない

    藤田洋史, 土生田宗憲, 服部高子, 久保田聡, 大内淑代

    第127回日本解剖学会  2022.3.28 

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    Event date: 2022.3.27 - 2022.3.29

    Presentation type:Poster presentation  

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  • 変形性股関節症とCCN3発現の相関

    廣瀬一樹, 中田英二, 服部高子, 鉄永智紀, 山田和希, 佐藤嘉洋, 桑原実穂, 滝川正春, 久保田聡, 尾崎敏文

    第34回日本軟骨代謝学会  2022.2.18 

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    Event date: 2022.2.18 - 2022.2.19

    Presentation type:Oral presentation (general)  

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  • メトホルミンによる非コードRNA誘導と軟骨細胞分化促進作用

    近藤 星, 服部高子, 桑原実穂, Fu Shanqi, 西田 崇, 薬師寺翔太, 吉岡洋祐, 森谷徳文, 飯田征二, 滝川正春, 久保田聡

    第34回日本軟骨代謝学会  2022.2.18 

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    Event date: 2022.2.18 - 2022.2.19

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  • 変形性股関節症とCCN3の相関

    廣瀬一樹, 廣瀬一樹, 中田英二, 鉄永智紀, 山田和希, 小浦卓, 井上智博, 服部高子, 滝川正春, 久保田聡, 尾崎敏文

    日本股関節学会学術集会プログラム・抄録集  2022 

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  • メトホルミンの軟骨細胞におけるUCA1誘導をともなった分化促進作用

    近藤 星, 服部高子, 桑原実穂, Fu Shanqi, 西田 崇, 吉岡洋祐, 森谷徳文, 飯田征二, 滝川正春, 久保田聡

    第44回日本分子生物学会年会  2021.12.1 

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    Event date: 2021.12.3

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  • マウス副腎におけるUCP1の発現は寒冷刺激により上昇しない.

    藤田 洋史, 土生田 宗憲, 服部 高子, 久保田 聡, 公文 裕己, 大内 淑代

    第44回日本分子生物学会年会, 横浜(ハイブリッド開催)(口演)(P)[2P-0610]  2021.12 

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  • 変形性肩関節症モデルとしてのCCN3過剰発現マウス

    廣瀬一樹, 中田英二, 服部高子, 鉄永智紀, 山田和希, 佐藤嘉洋, 桑原実穂, 滝川正春, 久保田聡, 尾崎敏文

    第39回日本骨代謝学会  2021.10.18 

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    Event date: 2021.11.30

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  • CCN3は関節軟骨の加齢変性を促進する

    桑原実穂, 武内聡子, 近藤 星, Fu Shanqi, 大野充昭, 古松毅之, 中田英二, 滝川正春, 久保田聡, 服部高子

    第39回日本骨代謝学会  2021.10.8 

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    Event date: 2021.11.30

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  • メトホルミンのUCA1誘導および軟骨細胞分化促進作用

    近藤 星, 服部高子, 桑原実穂, Fu Shanqi, 西田 崇, 吉岡洋祐, 森谷徳文, 飯田征二, 滝川正春, 久保田聡

    第94回日本生化学会大会  2021.11.3 

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  • Cysltr1遺伝子変異は破骨細胞分化と炎症性骨破壊に影響しない

    藤田 洋史, 土生田 宗憲, 大野 充昭, 大橋 俊孝, 服部 高子, 久保田 聡, 大内 淑代

    第94回日本生化学会大会, 横浜(Web開催)[P-925]  2021.11  (公社)日本生化学会

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    Language:Japanese  

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  • OCN3は関節軟骨の加齢性変性を促進する

    桑原 実穂, 近藤 星, Fu Shanqi, 大野 充昭, 古松 毅之, 中田 英二, 滝川 正春, 久保田 聡, 服部 高子

    日本骨代謝学会学術集会プログラム抄録集  2021.10  (一社)日本骨代謝学会

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    Language:Japanese  

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  • CCN3は関節軟骨の加齢性変性を促進する

    桑原 実穂, 近藤 星, Fu Shanqi, 大野 充昭, 古松 毅之, 中田 英二, 滝川 正春, 久保田 聡, 服部 高子

    日本骨代謝学会学術集会プログラム抄録集  2021.10  (一社)日本骨代謝学会

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    Language:Japanese  

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  • 成体神経筋接合部でのCCN ファミリーの役割

    大河原美静, 服部高子, 久保田聡, 伊藤美佳子, 増田章男, 滝川正春, Karen M. Lyons, 大野欽司

    第12回日本CCNファミリー研究会, 岡山(Web開催)  2021.9 

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  • Circadian production of melatonin and its receptors influence metabolism and rhythmic gene expression in chondrocytes

    Shanqi Fu, 桑原実穂, 内田瑶子, 近藤星, 池亀美華, 丸山雄介, 服部淳彦, 林大智, 下村侑司, 高垣安紗美, 西田崇, 久保田聡, 服部高子

    第62回 日本生化学会 中国・四国支部例会 2021, 9, 10-11, 岡山 (WEB開催)  2021.9 

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  • 副腎髄質におけるUCP1タンパク質発現のUCP1レポーターマウスを用いた検証(UCP1-reporter mice reveal UCP1 protein expression in the adrenal medulla)

    Fujita Hirofumi, Habuta Munenori, Hattori Takako, Kubota Satoshi, Kumon Hiromi, Ohuchi Hideyo

    The Journal of Physiological Sciences  2021.8  (一社)日本生理学会

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    Language:English  

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  • 変形性肩関節症とCCN3発現上昇との相関について

    廣瀬 一樹, 中田 英二, 服部 高子, 鉄永 智紀, 山田 和希, 佐藤 嘉洋, 桑原 実穂, 滝川 正春, 久保田 聡, 尾崎 敏文

    日本整形外科学会雑誌  2021.8  (公社)日本整形外科学会

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    Language:Japanese  

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  • non-coding RNAを介したメトホルミンの抗線維化作用の解析

    近藤 星, 服部 高子, 桑原 実穂, Fu Shanqi, 西田 崇, 吉岡 洋祐, 森谷 徳文, 飯田 征二, 滝川 正春, 久保田 聡

    日本口腔科学会雑誌  2021.7  (NPO)日本口腔科学会

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    Language:Japanese  

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  • 腸内細菌の有無が胎児内軟骨成長に与える影響

    内田瑶子, 服部高子, 福原大樹, Fu Shanqi, 近藤 星, 桑原実穂, イスラム モニルル, 片岡広太, 江國大輔, 久保田聡, 森田 学

    第33回日本軟骨代謝学会、2021, 3, 26-7,岐阜 (WEB開催) (P)  2021.3 

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  • Plasma melatonin enhances growth, inhibits maturation, and adjusting circadian rhythm of melatonin production in chondrocytes

    Fu Shanqi, Kuwahara Miho, Uchida Yoko, Kondo Sei, Nishida Takashi, Ikegame Mika, Maruyama Yusuke, Hattori Atsuhiko, Takagaki Asami, Shimomura Yuji, Hayashi Daichi, Kubota Satoshi, Hattori Takako

    第33回日本軟骨代謝学会2021, 3, 26-7, 岐阜 (WEB開催)(O)  2021.3 

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  • 変形性肩関節症とCCN3発現上昇との相関について

    廣瀬一樹, 中田英二, 服部高子, 鉄永智紀, 山田和希, 佐藤嘉洋, 桑原実穂, 滝川正春, 久保田聡, 尾崎敏文

    移植(Web)  2021 

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  • メトホルミンの軟骨細胞分化に対する作用の解析

    近藤 星, 服部 高子, 桑原 実穂, Fu Shanqi, 森谷 徳文, 飯田 征二, 滝川 正春, 久保田 聡

    岡山歯学会雑誌  2020.12  岡山歯学会

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    Language:Japanese  

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  • ヒトの関節軟骨における周期的遺伝子発現に対するメラトニンの影響(Effect of melatonin on rhythmic gene expression in human articular cartilage)

    フシャンキ, 桑原 実穂, 内田 瑶子, 近藤 星, 西田 崇, 池亀 美華, 久保田 聡, 服部 高子

    日本骨代謝学会学術集会プログラム抄録集  2020.10  (一社)日本骨代謝学会

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    Language:English  

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  • 発生と疾患にみる新たな細胞間コミュニケーション 母体腸内細菌叢の有無が胎児骨格形成に与える影響

    福原 瑶子, 服部 高子, 池亀 美華, 久保田 聡, 岡村 裕彦

    Journal of Oral Biosciences Supplement  2020.9  (一社)歯科基礎医学会

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    Event date: 2020.9

    Language:Japanese  

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  • ヒト関節軟骨細胞における周期的遺伝子発現に対するメラトニンの影響(Effect of melatonin on rhythmic gene expression in human articular chondrocytes)

    Fu Shanqi, 桑原 実穂, 内田 瑶子, 林 大智, 下村 侑司, 高垣 安紗美, 西田 崇, 中田 英二, 古松 毅之, 近藤 星, 丸山 雄介, 服部 淳彦, 久保田 聡, 服部 高子

    日本生化学会大会プログラム・講演要旨集  2020.9  (公社)日本生化学会

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    Event date: 2020.9

    Language:English  

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  • Cysltr1ノックアウトマウスを用いたシステイニルロイコトリエン受容体1の骨粗鬆症モデルにおける機能解明

    藤田洋史, 安藤碧, 大野充昭, 土生田宗憲, 服部高子, 久保田聡, 大内淑代

    日本解剖学会総会・全国学術集会講演プログラム・抄録集  2020 

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  • The investigation of the impact of mother gut microbiome of the endochondral ossification of embryo.

    福原瑶子, 服部高子, 池亀美華, 久保田聡, 岡村裕彦

    Journal of Oral Biosciences Supplement (Web)  2020 

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  • 軟骨細胞は加齢にともなってCCN3を高発現し,その過剰発現は軟骨加齢を促進する

    桑原実穂, 武内聡子, 近藤星, FU Shanqi, 大野充昭, 古松毅之, 中田英二, 滝川正春, 久保田聡, 服部高子

    日本分子生物学会年会プログラム・要旨集(Web)  2019.12 

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  • 長鎖(約6kb)IssODNおよびCRISPR/Cas9を用いたヒト科霊長類特異的lncRNAのマウス受精卵へのエレクトロポレーションによるノックインの試み

    近藤 星, 桑原 実穂, Fu Shanqi, 武内 聡子, 池田 健司, 石川 崇典, 大野 充昭, 西田 崇, 久保田 聡, 服部 高子

    日本生化学会大会プログラム・講演要旨集  2019.9  (公社)日本生化学会

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    Event date: 2019.9

    Language:Japanese  

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  • 軟骨細胞は松果体由来のメラトニン刺激で概日リズムを持ってメラトニンを産生し、増殖を促進し、肥大化を抑制する

    Fu Shanqi, 桑原 実穂, 内田 瑶子, 近藤 星, 西田 崇, 池亀 美華, 久保田 聡, 服部 高子

    日本骨代謝学会学術集会プログラム抄録集  2019.9  (一社)日本骨代謝学会

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    Language:English  

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  • 長鎖(約6kb)lssODNおよびCRISPR/Cas9を用いたヒト科霊長類特異的lncRNAのマウス受精卵へのエレクトロポレーションによるノックインの試み

    近藤星, 桑原実穂, FU Shanqi, 武内聡子, 池田健司, 石川崇典, 大野充昭, 西田崇, 久保田聡, 服部高子

    日本生化学会大会(Web)  2019.9  (公社)日本生化学会

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    Event date: 2019.9

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  • 破骨細胞におけるロイコトリエン系の機能解析:CRISPR-Cas9を用いたcysltr1ノックアウトマウスの作製

    藤田洋史, 土生田宗憲, 服部高子, 久保田聡, 大内淑代

    日本解剖学会総会・全国学術集会講演プログラム・抄録集  2019 

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  • 長鎖(約6kb)ssODNおよびCRISPR/Cas9を用いたヒト科霊長類特異的lncRNAのマウス受精卵へのエレクトロポレーションによる高効率ノックインの試み

    近藤星, 桑原実穂, FU Shanqi, 池田健司, 石川崇典, 大野充昭, 西田崇, 久保田聡, 服部高子

    日本分子生物学会年会プログラム・要旨集(Web)  2018.11 

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  • CCN2とRab14の相互作用が骨・軟骨細胞の基質産生に及ぼす役割

    星島 光博, 服部 高子, 田中 智代, 上岡 寛, 滝川 正春

    日本矯正歯科学会大会プログラム・抄録集  2018.10  (公社)日本矯正歯科学会

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  • ヒト科霊長類特異的lncRNAのエレクトロポレーションによる マウス受精卵への効率的なノックインの試み

    近藤 星、桑原実穂、Fu Shanqi、池田健司、石川崇典、大野充昭 、西田 崇 、久保田聡 、服部高子

    ブレインストーミング2018 

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    Event date: 2018.9.15

    Language:Japanese   Presentation type:Poster presentation  

    Venue:瀬戸内市  

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  • 軟骨におけるメラトニンとその受容体の日周的合成は軟骨の律動的遺伝子発現に影響を及ぼす(Circadian production of melatonin and its receptors in cartilage influences chondrocyte rhythmic gene expression)

    Fu Shanqi, 桑原 実穂, 内田 瑶子, 林 大智, 下村 侑司, 高垣 安紗美, 西田 崇, 丸山 雄介, 池亀 美華, 服部 淳彦, 服部 高子, 久保田 聡

    日本生化学会大会プログラム・講演要旨集  2018.9  (公社)日本生化学会

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  • ゲノム編集マウスを用いた破骨細胞分化におけるロイコトリエン合成関連遺伝子の機能解析

    藤田洋史, 長尾僚祐, 土生田宗憲, 服部高子, 久保田聡, 大内淑代

    日本解剖学会総会・全国学術集会講演プログラム・抄録集  2018 

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  • メトホルミンによるUCA1を介した軟骨保護作用の解析

    近藤 星, 服部高子, 桑原実穂, Fu Shanqi, 西田 崇, 薬師寺翔太, 吉岡洋祐, 森谷徳文, 飯田征二, 滝川正春, 久保田聡

    第42回岡山歯学会  2021.11.28 

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Industrial property rights

  • がんの治療又は予防剤

    滝川 正春, 服部 高子, 皆川 吉, 瀬戸 泰裕, 綱 美香, 原田 義孝, 高久 学, 安田 秀世

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    Applicant:日本製粉株式会社, 国立大学法人 岡山大学

    Application no:特願2013-006973  Date applied:2013.1.18

    Announcement no:特開2013-166751  Date announced:2013.8.29

    J-GLOBAL

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  • がんの治療又は予防剤

    滝川 正春, 服部 高子, 皆川 吉, 瀬戸 泰裕, 綱 美香, 原田 義孝, 高久 学, 安田 秀世

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    Applicant:日本製粉株式会社, 国立大学法人 岡山大学

    Application no:特願2013-006973  Date applied:2013.1.18

    Announcement no:特開2013-166751  Date announced:2013.8.29

    Patent/Registration no:特許第6187960号  Date registered:2017.8.10  Date issued:2017.8.10

    J-GLOBAL

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Works

  • 第43回岡山歯学会・学術集会、岡山歯学会優秀論文賞: Roles of interaction between CCN2 and Rab14 in aggrecan production by chondrocytes.

    Hoshijima, M, Hattori, T, Aoyama, E, Nishida, T, Kubota, S, Takigawa, M

    2022.12.11

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  • 第45回日本分子生物学会 日本生物物理学会 共催、サイエンスピッチアワード・優秀発表賞: 軟骨細胞におけるメトホルミンによるlong non-coding RNA, UCA1およびCCN2の発現制御

    近藤 星, 服部高子, 桑原実穂, Fu Shanqi, 西田 崇, 薬師寺翔太, 吉岡洋祐, 森谷徳文, 飯田征二, 滝川正春, 久保田聡

    2022.12.2

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  • 第42回岡山歯学会・学術集会、岡山歯学会奨励論文賞

    Fu Shanqi, Kuwahara Miho, Uchida Yoko, Kondo Sei, Nishida Takashi, Ikegame Mika, Maruyama Yusuke, Hattori Atsuhiko, Takagaki Asami, Shimomura Yuji, Hayashi Daichi, Kubota Satoshi, Hattori Takako

    2021.10.28

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  • 第91回日本生化学会大会若手優秀発表賞

    Shanqi Fu, 桑原 実穂, 内田 瑶子, 林 大智, 下村 侑司, 高垣 安紗美, 西田 崇, 丸山 雄介, 池亀 美華, 服部 淳彦, 服部 高子, 久保田 聡

    2018.9.24
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    2018.9.26

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  • 平成29年度至誠会基礎医学研究助成渡辺慶子賞

    服部高子

    2017

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  • 第55回歯科基礎医学会学生ポスター賞

    角谷宏一, 服部高子, 桑原実穂, 大野充昭, 星島光博, 窪木拓男, 滝川正春

    2013.9.20
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    2013.9.21

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  • 先端歯学スクール2012

    星島光博, 服部高子

    2012.9.20
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    2012.9.21

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  • Finalist of the Hatton Award competition - 59th meeting of the Japanese Association for Dental Research (JADR) – 2011

    Hara ES, Ono M, Kubota S, Sonoyama W, Oida Y, Hattori T, Nishida T, Furumatsu T, Ozaki T, Takigawa M, Kuboki T

    2011.10.8
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    2011.10.9

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  • 2011 ASBMR Young Investigator Travel Grant

    Mitsuhiro Hoshijima, Takako Hattori, Eriko Aoyama, Takashi Nishida, Takashi Yamashiro, Masaharu Takigawa

    2011.9.16
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    2011.9.20

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  • 第4回日本CCNファミリー研究会若手国際学術奨励賞受賞講演

    Kazumi Kawata, Satoshi Kubota, Takanori Eguchi, Eriko Aoyama, Seiji Kondo, Takako Hattori, Masaharu Takigawa

    2011.8.26
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    2011.8.27

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  • 第29回日本骨代謝学会優秀ポスター

    Emilio Satoshi Hara, Mitsuaki Ono, Satoshi Kubota, Wataru Sonoyama, Takako Hattori, Masaharu Takigawa, Takuo Kuboki

    2011.7.28
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    2011.7.30

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  • QOL2011 国際シンポジウム招待講演

    2011

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    Work type:Artistic work  

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  • Faculty of 1000 Medicine

    2010

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    Work type:Artistic work  

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  • 先端歯学スクール2010優秀発表賞

    2010

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    Work type:Artistic work  

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  • Faculty of 1000 Biology

    2010

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  • 2010 ICCNS-SPRINGER Award

    2010

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  • 第27回日本骨代謝学会優秀ポスター賞

    2009

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  • 2nd Joint Meeting of the IBMS and the ANZBMS トラベルアワード講演

    2009

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  • 平成21年度 特別教育研究経費「口腔からQOL向上を目指す連携研究」に関連した研究スカラシップ事業に基づく研究

    2009

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Awards

  • 岡山歯学会優秀論文賞

    2022.12  

    Hoshijima, M, Hattori, T, Aoyama, E, Nishida, T, Kubota, S, Takigawa, M

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  • サイエンスピッチアワード・優秀発表賞

    2022.12   日本分子生物学会 日本生物物理学会共催   軟骨細胞におけるメトホルミンによるlong non-coding RNA, UCA1およびCCN2の発現制御

    近藤 星、 服部高子、桑原実穂、Fu Shanqi、西田 崇、薬師寺翔太、吉岡洋祐、森谷徳文、飯田征二、滝川正春、久保田聡

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  • 岡山歯学会奨励論文賞

    2021.11   岡山歯学会  

    Fu Shanqi, Kuwahara Miho, Uchida Yoko, Kondo Sei, Nishida Takashi, Ikegame Mika, Maruyama Yusuke, Hattori Atsuhiko, Takagaki Asami, Shimomura Yuji, Hayashi Daichi, Kubota Satoshi, Hattori Takako

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  • 第91回日本生化学会大会若手優秀発表賞

    2018.9   日本生化学会大会  

    Shanqi Fu, 桑原 実穂, 内田 瑶子, 林 大智, 下村 侑司, 高垣 安紗美, 西田 崇, 丸山 雄介, 池亀 美華, 服部 淳彦, 服部 高子, 久保田 聡

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  • 平成29年度至誠会基礎医学研究助成渡辺慶子賞

    2017   一般社団法人 至誠会   低身長治療のみでなく関節機能維持によるアンチエイジング療法の開発を目的とした軟骨組織の概日リズム形成機構の解明

    服部高子

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  • 平成28年度公益財団法人両備檉園記念財団研究助成

    2016   公益財団法人両備檉園記念財団   軟骨組織におけるCCNファミリー遺伝子群の濃度調節による軟骨成長促進と関節機能維持の試み

    服部高子

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  • 平成26年度成長科学協会研究助成

    2014   公益財団法人 成長科学協会   骨伸長促進効果を有する結合組織成長因子CTGF/CCN2の低身長治療への応用のための基礎研究

    服部高子

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  • 学生ポスター賞

    2013.9   第55回歯科基礎医学会  

    角谷宏一, 服部高子, 桑原実穂, 大野充昭, 星島光博, 窪木拓男, 滝川正

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  • 先端歯学スクール2012

    2012.9   先端歯学スクール2012   CCN2とCCN3のホモおよびヘテロダイマーが軟骨細胞の基質合成に及ぼす影響

    星島光博

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  • Finalist of the Hatton Award competition

    2011.10   59th meeting of the Japanese Association for Dental Research (JADR)  

    Hara ES, Ono M, Kubota S, Sonoyama W, Oida Y, Hattori T, Nishida T, Furumatsu T, Ozaki T, Takigawa M, Kuboki T

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  • ASBMR Young Investigator Travel Grant

    2011.9   ASBMR 2011 Annual Meeting  

    Mitsuhiro Hoshijima, Takako Hattori, Eriko Aoyama, Takashi Nishida, Takashi Yamashiro, Masaharu Takigawa

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  • 若手国際学術奨励賞

    2011.8   第4回日本CCNファミリー研究会  

    Kazumi Kawata, Satoshi Kubota, Takanori Eguchi, Eriko Aoyama, Seiji Kondo, Takako Hattori, Masaharu Takigawa

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  • 優秀ポスター賞

    2011.7   日本骨代謝学会   Harmine, an inducer of CCN2/CTGF, promotes chondrogenesis and suppresses TNF-alpha-induced inflammatory response

    Emilio Satoshi Hara, Mitsuaki Ono, Satoshi Kubota, Wataru Sonoyama, Takako Hattori, Masaharu Takigawa, Takuo Kuboki

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  • QOL2011 国際シンポジウム招待講演

    2011  

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    Country:Japan

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  • 先端歯学スクール2010優秀発表賞

    2010  

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    Country:Japan

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  • Faculty of 1000 Biology

    2010  

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    Country:Japan

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  • Faculty of 1000 Medicine

    2010  

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  • Faculty of 1000 Biology: evaluations for Hattori T et al

    2010  

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    Country:Japan

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  • Faculty of 1000 Medicine: evaluations for Hattori T et al

    2010  

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  • 2010 ICCNS-SPRINGER Award

    2010  

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Research Projects

  • Development of dropletomics that clarifies transcriptional regulation under liquid-liquid phase separation

    Grant number:23K17439  2023.06 - 2027.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Research (Pioneering)

    久保田 聡, 西田 崇, 服部 高子, 高江洲 かずみ, 滝川 正春, 青山 絵理子, 大野 充昭

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    Grant amount:\25740000 ( Direct expense: \19800000 、 Indirect expense:\5940000 )

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  • 非コードRNAを介した新たな軟骨ホメオスタシスとその変性メカニズムの解明

    Grant number:22K10218  2022.04 - 2025.03

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    森谷 徳文, 滝川 正春, 久保田 聡, 服部 高子, 西田 崇, 近藤 星

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    Grant amount:\4160000 ( Direct expense: \3200000 、 Indirect expense:\960000 )

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  • 象牙芽細胞の表面に突き出た細胞小器官の機能解析と象牙質再生への応用

    Grant number:22K10075  2022.04 - 2025.03

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    高江洲 かずみ, 服部 高子, 青山 絵理子, 滝川 正春, 西田 崇, 久保田 聡

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    Grant amount:\4290000 ( Direct expense: \3300000 、 Indirect expense:\990000 )

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  • Inverse genetics: A new methodology for the identification of key genes of somatic cell differentiation

    Grant number:21K19603  2021.07 - 2023.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Research (Exploratory)

    久保田 聡, 西田 崇, 服部 高子, 高江洲 かずみ, 青山 絵理子, 滝川 正春, 大野 充昭

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    Grant amount:\6500000 ( Direct expense: \5000000 、 Indirect expense:\1500000 )

    初年度である本年度は、本研究で提唱する「インバース・ジェネティクス方法論」を、軟骨細胞を用いて検証することを第一の目的と定め研究を進めた。当初の予定ではマウス肋軟骨細胞を用いる予定であったが、長鎖非コードRNA (lncRNA) 遺伝子の数がはるかに多いこと、およびフィーダー細胞としてマウス由来SNL細胞を使うことを考慮しヒト軟骨細胞を用いた検討から開始することとした。理論上は可能だが軟骨細胞からiPS細胞を作成できたという報告はまだない。したがってまず山中4因子 (OSKM) を強制発現するレンチウイルスベクターを作成し、ヒト軟骨細胞に導入、リプログラミングが起こるかどうかをコロニー形成を指標に検討した。その結果OSKM導入発現2週間後には多数のコロニーの形成が見られ、軟骨細胞もiPS細胞化しうることが確認された。この結果を受けて、iPS干渉法によって仮説の妥当性とSOX9遺伝子の軟骨細胞分化の機能確認に進んだ。すなわち軟骨細胞にOSKMに加えてSOX9を発現させることでリプログラミングが阻止されるかを検証した。その結果SOX9発現によって形成されるコロニーは減少したがゼロにはならなかった。これはSOX9が単独で軟骨細胞分化を決定しているのではないためと考えている。そして次にシングルセル解析に進むにあたっては、解析前にフィーダー細胞を除去する必要がある。そのため以上の研究に並行して、蛍光色素mCherryを発現するSNL細胞を新たに樹立し、フローサイトメトリーで除去するシステムを整えてきた。ここまでは順調であったが、この実験システムではリプログラミング効率が十分ではなく、シングルセル解析で有意な結果を得るために必要なOSKM導入細胞数の確保が難しいことが分かってきた。そこで最近開発された一体型山中因子発現ウイルスベクターを試したところ、予備実験で飛躍的に高い導入効率が得られた。来年度はこのシステムを用いて研究を先に進める予定である。

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  • Regulation of skeletogenesis by long noncoding RNAs through CCN2

    Grant number:21H03105  2021.04 - 2025.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    久保田 聡, 西田 崇, 服部 高子, 高江洲 かずみ, 滝川 正春, 青山 絵理子

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    Grant amount:\17160000 ( Direct expense: \13200000 、 Indirect expense:\3960000 )

    本研究を支える2つの柱は、cellular communication network factor 2 (CCN2) 遺伝子をトランスに制御する長鎖非コードRNA (lncRNA) であるurothelial cancer associated 1 (UCA1) と、シスに制御するanti-CCN2 3'-UTR RNA (ACUR) である。
    まずUCA1については、当該lncRNAの作動エレメント、つまり軟骨細胞分化を促進するRNA上の機能領域を突き止めるためin silicoでUCA1の構造を予測し、順に欠損させた3つの変異体を発現するシステムを、レンチウイルスベクターを用いて構築し、それらベクターを使って標的であるマウスATDC5細胞でこれら変異体を強制発現できることを確認できた。またUCA1が吸着しうるmiRNAを探索し、現在までに37のmiRNAをUCA1によって軟骨細胞内で制御されうる分子として特定できた。さらに新たな展開として、UCA1が骨芽細胞機能に与える影響を、軟骨細胞と同じ戦略、すなわちUCA1を持たないマウスMC3T3-E1細胞にレンチウイルスベクターで強制発現させ、骨芽細胞マーカー遺伝子の発現定量やアルカリホスファターゼ染色で評価した。しかしながら軟骨細胞とは異なり骨芽細胞形質はUCA1の影響を受けなかった。以前の研究で、間葉系幹細胞が骨芽細胞へ分化する際、UCA1発現は減少することも確認している。以上の所見は、UCA1が軟骨細胞において高度に特異的な機能を発揮していることを示唆している。
    そしてACURについては、センスRNA、つまりCCN2 RNA には影響を与えることなくアンチセンスRNAのみを、RNase H活性により特異的に分解するGapmeRを5種類設計・合成し、ヒト軟骨細胞様HCS-2/8細胞に導入して関連遺伝子発現量を評価した。その結果、5種のうち2種のGapmeRによって効率よくACURのサイレンシングが起こることが確認され、その状況下ではCCN2遺伝子ばかりでなく、軟骨細胞マーカー遺伝子も抑制される傾向にあった。つまり骨格形成に対してインパクトを与えている可能性が濃厚となった。

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  • 長鎖非コードRNAによる骨細胞メカニカルストレス応答制御機構の解明

    Grant number:21K10189  2021.04 - 2024.03

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    石川 崇典, 宮脇 正一, 前田 綾, 大賀 泰彦, 久保田 聡, 西田 崇, 服部 高子, 高江洲 かずみ

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    Grant amount:\4160000 ( Direct expense: \3200000 、 Indirect expense:\960000 )

    最近、タンパク質をコードしない長鎖非コードRNAが様々な生理的機能に関与していることが明らかとなっている。しかしながら、矯正歯科治療における歯の移動において極めて重要な生体反応である、骨細胞のメカニカルストレス応答に関与するとされる長鎖非コードRNAの報告はまだない。そこで、本研究では骨細胞のメカニカルストレス応答下で機能する長鎖非コードRNAを特定し、その詳細な分子機構を明らかにすることを目的とし、研究を実施している。
    目的とする長鎖非コードRNAを特定するため、マイクロアレイによる網羅的遺伝子発現解析を予定しており、初年度はまず実施するサンプルの条件を検討した。骨細胞様細胞株MLO-Y4細胞を培養し、同細胞に様々な種類のメカニカルストレスを負荷後、同サンプルを回収し、骨芽細胞マーカー遺伝子および骨芽細胞分化に関与しているとされる長鎖非コードRNAを定量RT-PCRにより評価し、マイクロアレイを実施するサンプルの選定を行った。初年度末の時点で概ね本作業は完了しており、今後はコントロール群と比較し遺伝子変動の大きかった方法でメカニカルストレスを付与したMLO-Y4細胞を準備し、網羅的遺伝子発現解析を実施していく。同サンプルの解析結果より、特定の長鎖非コードRNAの遺伝子発現の上昇もしくは低下が確認できると考えており、2年目以降では、その中で特に遺伝子発現の変動が多かったRNAをin vitroにてノックダウンおよび強制発現させ、骨代謝マーカー遺伝子の発現変動を確認し詳細な機能を調査することとしている。

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  • 変形性足関節症におけるCCN3を介した新たな軟骨細胞老化制御機構の解明

    Grant number:21K09280  2021.04 - 2024.03

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    雑賀 建多, 服部 高子, 中田 英二, 二川 摩周, 尾崎 敏文, 久保田 聡

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    Grant amount:\4290000 ( Direct expense: \3300000 、 Indirect expense:\990000 )

    変形性足関節症 (osteoarthritis of the ankle; OA of the ankle)の患者では痛みや歩行障害により日常生活動作が著しく低下する。我々はOA関連遺伝子の探索を行い、軟骨組織の発生・分化・再生過程において多様な生理機能を持つCellular Communication Network Factor (CCN)フ ァミリー遺伝子のうち、CCN3がヒトから得られた関節軟骨細胞で加齢とともに有意に増加していることを認めた。また、酸化ストレス刺激により老化を誘導した軟骨細胞でCCN3 発現の上昇を認めた。そこで、これらの結果をもとに足関節においてCCN3が軟骨細胞の老化によるOAを促進するか検討し、足関節の軟骨細胞において、CCN3を介した加齢性変性に対する分子メカニズムを解明することを目的としている。
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    研究実施計画に基づき、足関節固定術や人工足関節置換術時に軟骨組織を採取し解析を行なっている。令和3年度は、まず並行して行なっている股関節軟骨研究を進めた。すなわち、Normal群とOA群を荷重部と非荷重部で分け、それぞれの組織をサフラニンOで染色した。肉眼的にOA群荷重部で明らかな軟骨層の菲薄化が確認できた。また、培養した軟骨細胞のmRNAをReal-time PCRを使用しCCN2, 3とADAMTS5で評価した。CCN3, ADAMTS5で荷重、非荷重関係なしにOA群で有意に上昇を認めた。また、両群において年齢との相関はなかった。さらに、組織より直接抽出した軟骨細胞のmRANを評価した。荷重、非荷重に関与することなくそれぞれの因子でOA群において有意に上昇を認めた。また、両群において年齢との相関はなかった。

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  • 新規軟骨老化促進因子CCN3の加齢に伴った発現誘導と細胞周期停止機構の解明

    Grant number:21K09815  2021.04 - 2024.03

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    服部 高子, 久保田 聡, 西田 崇, 高江洲 かずみ

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    Grant amount:\4160000 ( Direct expense: \3200000 、 Indirect expense:\960000 )

    1.胎生期から出生後37週(8.6ヶ月齢)までの様々な時期のマウス肋軟骨組織から初代培養軟骨細胞を単離し、遺伝子発現の変化を調べると、CCN family member 3 (CCN3) mRNAとともに細胞周期停止因子p21, p53、senescence-associated secretory phenotype (SASP)因子であるIL-6, IL-8 mRNAの発現レベルと軟骨細胞採取時のマウスの加齢状態との間に強い正の相関があることがわかった。また、CCN3抗体を用いた1ヶ月から7ヶ月齢のマウス膝関節の免疫染色でも、加齢とともに強い染色性が観察された。2.ヒト患者由来初代培養軟骨細胞、ラット培養軟骨細胞株RCSに酸化ストレスとしてH2O2を添加し、人工的に誘発した老化軟骨細胞においてCCN3 mRNAの有意な発現上昇とともに、p21,p53の発現上昇、肥大軟骨マーカーである10型コラーゲン、マトリックスメタロプロテナーゼ13、アグリカン分解酵素ADAMTS5 mRNAの発現誘導が認められ、CCN3、P53の誘導は蛋白レベルでも確かめられた。この時、senescence-associated (SA)-β galactosidaseの活性化も確認された。3.RCS細胞にCCN3を発現ベクターの導入により過剰発現させるとp21プロモータ活性が上昇した。4.2週齢マウス膝関節より単離された初代培養軟骨細胞およびRCS細胞に組換えCCN3蛋白を添加するとp21, p53 mRNAが誘導された。これらのことからCCN3の発現上昇によっても細胞周期停止因子の誘導による老化が誘発されることが明らかとなった。5.軟骨組織特異的にCCN3を発現するトランスジェニックマウスの関節軟骨では、早期に関節変性が誘導され、このマウスの肋軟骨組織から単離した初代培養軟骨細胞では細胞周期停止因子群、SASP因子群の発現が上昇していた。6.ヒト患者由来関節組織から単離した初代培養軟骨細胞においてCCN3, p21,p53 mRNAの発現レベルと年齢との間に強い正の相関が観察された。

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  • CCN2の転写因子様機能を介した線維症のキープレイヤー筋線維芽細胞分化機構の解明

    Grant number:20K09889  2020.04 - 2023.03

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    西田 崇, 滝川 正春, 久保田 聡, 服部 高子, 青山 絵理子, 高江洲 かずみ

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    Grant amount:\4290000 ( Direct expense: \3300000 、 Indirect expense:\990000 )

    線維性疾患は組織内にコラーゲンが過剰に沈着し、正常な組織機能が損なわれる慢性疾患である。近年、筋線維芽細胞が線維化のキープレイヤーとして注目されているが、その分化機構は未だ不明である。本研究課題の目的は線維化の進行に重要な役割を担うと考えられているCellular communication network factor 2 (CCN2)が筋線維芽細胞の分化にどのように関わっているのかをイントラクリン作用の観点から解明することである。当該年度では、未分化間葉系細胞株C3H10T1/2細胞を用いてCCN2にイントラクリン様の作用を誘導し、筋線維芽細胞への分化に対する影響を解析した。以下にその結果を示す。
    1.シグナルペプチドを欠失したCCN2の発現プラスミド(SP-Ccn2)を構築し、C3H10T1/2細胞に遺伝子導入した。対照群としてシグナルペプチドを付加したCCN2の発現プラスミド(SP+Ccn2)を用いた。CCN2が核内に移行するかを蛍光免疫染色で調べた結果、SP+Ccn2を遺伝子導入した細胞ではCCN2が細胞質に局在したのに対し、SP-Ccn2を遺伝子導入した細胞ではCCN2は一部核内に見られた。
    2.1.で作製した発現プラスミドをC3H10T1/2細胞に遺伝子導入し、筋線維芽細胞分化に重要な転写因子であるPU.1の遺伝子発現レベルを定量RT-PCR法で解析した。結果、SP+Ccn2を遺伝子導入した群ではempty vectorを導入した群と変わらなかったが、SP-Ccn2を遺伝子導入した群はPU.1の遺伝子発現レベルが有意に上昇した。
    3.PU.1の標的分子であるテネイシンC及びPDGFの産生量をWestern blot解析で調べた結果、SP-Ccn2を導入した群で両分子の産生量の増加が見られた。

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  • Regulation of CCN2 by an endogenous UTR blocker and its biological significance

    Grant number:19K22716  2019.06 - 2021.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Research (Exploratory)

    Kubota Satoshi

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    Grant amount:\6370000 ( Direct expense: \4900000 、 Indirect expense:\1470000 )

    The CCN2 gene is expressed in chondrocytes and plays a critical role in mammalian skeletal development. The aim of this study is to clarify the function of a novel lncRNA entitled ACUR that covers the entire 3'-untranslated region of the CCN2 mRNA. First, we found that ACUR was expressed, not only in several types of cancer cells, but also in human chondrocytic cells and chondrocytes isolated from knee joints. ACUR expression was subsequently confirmed in a murine mesenchymal stem cell-like cells, which was repressed along with adipogenic differentiation. Interestingly, CCN2 mRNA expression was decreased upon adipogenic differentiation as well. ACUR was also detected in murine chondroblastic cells. However, in contrast, ACUR expression was increased during the course of chondrocytic differentiation. These findings indicate that ACUR is conserved between human and murine species and that this lncRNA contributes to chodrocytic differentiation, positively regulating the CCN2 gene.

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  • 細胞アンテナによる象牙質再生への道を拓く基礎研究

    Grant number:19K10109  2019.04 - 2023.03

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    高江洲 かずみ, 服部 高子, 青山 絵理子, 滝川 正春, 西田 崇, 久保田 聡

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    Grant amount:\4420000 ( Direct expense: \3400000 、 Indirect expense:\1020000 )

    日本人の平均寿命は年々伸びている反面、健康寿命は伸びていない。健康寿命を延長には咀嚼機能の維持が鍵となるため、歯牙の再生療法の開拓が望まれている。個々の歯牙の再建には象牙質の再生が必須であるが、自然状態での象牙質再生能力は不充分である。
    このため、象牙芽細胞の細胞外環境感知センサー、つまり〝一次繊毛”の形成や細胞周期の制御に機能するIntraflagellar transport (Ift) 88を機能制御することで、象牙質再生の実現を我々は目指している。理想的な形質・形態の象牙質を再生するためには、まず正常象牙質の形成過程を解明する必要がある。そのために、まず、1. 象牙芽前駆細胞の接着・増殖、2. 分化、3. 細胞極性の分子制御機構を検討する。その上で、象牙質再生法の開発を検討していく。
    現在までに、Ift 88をノックダウンした象牙芽前駆細胞であるsh-Ift88 KN-3細胞では、一次繊毛形成に関係なく、細胞接着能力や細胞増殖速度が抑制されることを確認している。本年度は、KN-3細胞において、IFT88が細胞接着や細胞増殖を調節する機構を検討するため、Fucci-S/G2/M Green expression KN-3細胞を作製し、細胞周期のモニタリングをArrayScanを用いて行った。その結果、sh-Ift88 KN-3細胞では、コントロールのKN-3細胞と比較して、Fucci-S/G2/M Greenの発現が抑制されていることが明らかとなった。

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  • 低身長治療のみでなく関節機能維持によるアンチエイジング療法の開発を目的とした軟骨組織の概日リズム形成機構の解明

    2017.10 - 2018.09

    至誠会  平成29年度至誠会基礎医学研究助成渡辺慶子賞 

    服部高子

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    Authorship:Principal investigator 

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  • Novel regulatory mechanism of endochondral ossification via CCN2-VASH1 axis

    Grant number:17H06885  2017.08 - 2019.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Research Activity Start-up

    MURASE Yurika, TAKIGAWA Masaharu, SATO Yasufumi, KUBOTA Satoshi, AOYAMA Eriko, SUZUKI Yasuhiro, HATTORI Takako, YOSHIDA Shoko, SASAKI Akira

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    Grant amount:\2730000 ( Direct expense: \2100000 、 Indirect expense:\630000 )

    The aim of this study is to investigate a novel regulatory mechanism of endochondral ossification by CCN2 and VASH1. We found that both CCN2 and VASH1 were localized in the hypertrophic chondrocyte layer. CCN2-silencing in chondrocytes reduced the expression of VASH1 and increased apoptotic cells, and its increase was suppressed by a ROS inhibitor, N-acetyl-L-cysteine. These results suggest that up-regulation of CCN2-VASH1 axis may suppress the elevation of ROS level that causes chondrocyte cell death/apoptosis and keep hypertrophic chondrocytes surviving until the terminal stage of chondrogenic differentiation.

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  • New potential of CCN2: Functional evaluation as a Warburg effector

    Grant number:17K19756  2017.06 - 2019.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Research (Exploratory)

    Kubota Satoshi

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    Grant amount:\6370000 ( Direct expense: \4900000 、 Indirect expense:\1470000 )

    As a result of the investigation with a chondrosarcoma cell line, we found that cellular ATP level was repressed by CCN2 silencing; whereas CCN2 expression was repressed by glycolytic inhibition vice versa. These findings indicate the property of CCN2 as a Warburg booster, which is more than a Warburg effector. Furthermore, through the evaluation of the effects of glycolytic inhibition on the gene expression of all of the CCN family members, we discovered that CCN3 was contrarily induced by glycolytic inhibition. Such CCN3 induction was not observed by the inhibition of aerobic ATP synthesis by mitochondria and thus depends on glycolytic activity in the cells. Collectively, it was clarified in this study that both CCN2 and CCN3 gene expression was under a tight regulation by glycolytic activity, which eventually determines the status of energy metabolism in tumor cells.

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  • Mechanism of onset of osteoarthritis caused by obesity and regulatory effects of CCN2

    Grant number:17K11641  2017.04 - 2020.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Nishida Takashi

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    Grant amount:\4680000 ( Direct expense: \3600000 、 Indirect expense:\1080000 )

    In this study, we showed that angiotensin II (ANG II) suppresses chondrocyte proliferation and differentiation as well as increased CCN2 production in dose-dependent manner. Based on our results using chondrocytes treated with losartan, which is a specific inhibitor of AT1R and those using AT1R-deficient chondrocytes, we clarified that the effects of ANG II are through AT1R. Furthermore, our data indicates that ANG II production is increased by CCN2 deficiency, suggesting that onset of osteoarthritis in Ccn2 deficient mice is involved with increased ANG II.

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  • The relationship of Sorcin and endochondral ossification

    Grant number:17K11635  2017.04 - 2020.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    河井 まりこ, 服部 高子

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    Grant amount:\4550000 ( Direct expense: \3500000 、 Indirect expense:\1050000 )

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  • Analysis of the initial mineralization in secondary ossification center by the Life Science and Material