Faculty Profiles - TAKIGAWA Masaharu

Papers - TAKIGAWA Masaharu

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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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

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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Matrix remodeling response of human periodontal tissue cells toward fibrosis upon nicotine exposure Reviewed

Hiroko Takeuchi-Igarashi, Satoshi Kubota, Toshiaki Tachibana, Etsuko Murakashi, Masaharu Takigawa, Masataka Okabe, Yukihiro Numabe

ODONTOLOGY 104 ( 1 ) 35 - 43 2016.1

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

It is widely accepted that fibrosis is frequently observed in the gingiva of smokers. However, the mechanisms by which smoking results in pathological changes in periodontal tissue that lead to fibrosis are not entirely clear. Our former report showed that type I collagen synthesis was promoted by nicotine via CCN family protein 2 in human periodontal tissue cells. Here, we evaluated other aspects of nicotine function from a viewpoint of extracellular matrix (ECM) remodeling. Human gingival fibroblasts (n = 4) and periodontal ligament cells (n = 3) were isolated. The cells were treated with nicotine at a variety of concentrations for 12-48 h. Modulators of matrix remodeling were measured using enzyme-linked immunosorbent assays. Cell migration and morphology were also evaluated. As a result, following treatment with 1 mu g/ml nicotine, tissue inhibitor of metalloproteinase-1 and transforming growth factor-beta 1 production in both cell lysates and supernatants, and matrix metalloproteinases-1 production in cell lysates, were significantly increased (p < 0.05). Compared to controls, cell migration was significantly inhibited (p < 0.005) by nicotine in a time-dependent manner. Electron microscopic analysis revealed the presence of a number of vacuoles in nicotine-treated cells. These results indicate that nicotine not only impairs fibroblast motility, and induces cellular degenerative changes, but also alters ECM-remodeling systems of periodontal cells. Induction of matrix remodeling molecules, combined with type I collagen accumulation, may account for the molecular mechanism of nicotine-induced periodontal fibrosis.

DOI： 10.1007/s10266-014-0177-y

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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

Language：English Publishing type：Research paper (scientific journal) Publisher：JOURNAL HARD TISSUE BIOLOGY

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.

DOI： 10.2485/jhtb.25.57

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CCN4/WISP-1 positively regulates chondrogenesis by controlling TGF-beta 3 function Reviewed

Yoshioka, Yuya, Ono, Mitsuaki, Maeda, Azusa, Kilts, Tina M., Hara, Emilio Satoshi, Khattab, Hany, Ueda, Junji, Aoyama, Eriko, Oohashi, Toshitaka, Takigawa, Masaharu, Young, Marian F., Kuboki, Takuo

Bone 83 162 - 170 2016

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

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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Physical interaction of CCN2 with diverse growth factors involved in chondrocyte differentiation during endochondral ossification Reviewed

Hany Mohamed Khattab, Eriko Aoyama, Satoshi Kubota, Masaharu Takigawa

JOURNAL OF CELL COMMUNICATION AND SIGNALING 9 ( 3 ) 247 - 254 2015.9

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

CCN family member 2 (CCN2) has been shown to promote the proliferation and differentiation of chondrocytes, osteoblasts, osteoclasts, and vascular endothelial cells. In addition, a number of growth factors and cytokines are known to work in harmony to promote the process of chondrogenesis and chondrocyte differentiation toward endochondral ossification. Earlier we showed that CCN2 physically interacts with some of them, suggesting that multiple effects of CCN2 on various differentiation stages of chondrocytes may be attributed to its interaction with these growth factors and cytokines. However, little is known about the functional interaction occurring between CCN2 and other growth factors and cytokines in promoting chondrocyte proliferation and differentiation. In this study we sought to shed light on the binding affinities between CCN2 and other essential growth factors and cytokines known to be regulators of chondrocyte differentiation. Using the surface plasmon resonance assay, we analyzed the dissociation constant between CCN2 and each of the following: TGF-beta 1, TGF-beta 3, IGF-I, IGF-II, PDGF-BB, GDF5, PTHrP, and VEGF. We found a strong association between CCN2 and VEGF, as well as a relatively high association with TGF-beta 1, TGF-beta 3, PDGF-BB, and GDF-5. However, the sensorgrams obtained for possible interaction between CCN2 and IGF-I, IGF-II or PTHrP showed no response. This study underlines the correlation between CCN2 and certain other growth factors and cytokines and suggests the possible participation of such interaction in the process of chondrogenesis and chondrocyte differentiation toward endochondral ossification.

DOI： 10.1007/s12079-015-0290-x

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

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

Journal of periodontal research 50 ( 4 ) 452 - 460 2015.8

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND AND OBJECTIVE: Tumor necrosis factor alpha (TNF-α) is a major cytokine implicated in various inflammatory diseases. The nature of the nuclear factors associated with human TNF-α gene regulation is not well elucidated. We previously identified a novel region located from -550 to -487 in human TNF-α promoter that did not contain the reported binding sites for nuclear factor kappa B (NF-κB) 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-α expression. MATERIAL AND METHODS: To identify DNA-binding proteins that bound to the target region of TNF-α 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-α expression. RESULTS: Several 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-α 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-α promoter fragments. Overexpression of TDP-43 in THP-1 cells resulted in an increase of TNF-α expression. Knockdown of TDP-43 in THP-1 cells downregulated TNF-α expression. CONCLUSION: We identified TDP-43 as one of the novel TNF-α factors and found that it bound to the LPS-responsive element in the TNF-α promoter to increase TNF-α expression.

DOI： 10.1111/jre.12227

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CCN2 enhances RANKL-induced osteoclast differentiation via direct binding to RANK and OPG Reviewed

Eriko Aoyama, Satoshi Kubota, Hany Mohamed Khattab, Takashi Nishida, Masaharu Takigawa

BONE 73 242 - 248 2015.4

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

CCN family protein 2/connective tissue growth factor (CCN2/CTGF) is a multi-potent factor for mesenchymal cells such as chondrocytes, osteoblasts, osteoclasts, and endothelial cells. CCN2 is also known as a modulator of other cytokines and receptors via direct molecular interactions with them. We screened additional factors binding to CCN2 and found receptor activator of NF-kappa B (RANK) as one of them. RANK is also known as TNF-related activation-induced cytokine (TRANCE) receptor, and its signaling plays a critical role in osteoclastogenesis. Notable affinity between CCN2 and RANK was confirmed by using surface plasmon resonance (SPR) analysis. In fact, CCN2 enhanced the RANK-mediated signaling, such as occurs in NF-kappa B, p38 and JNK pathways, in pre-osteoclastic RAW264.7 cells; whereas CCN2 had no influence on RANK RANK ligand (RANKL) binding. Moreover, CCN2 also significantly bound to osteoprotegerin (OPG), which is a decoy receptor of RANKL. Of note, OPG markedly inhibited the binding between CCN2 and RANK; and CCN2 canceled the inhibitory effect of OPG on osteoclast differentiation. These findings suggest CCN2 as a candidate of the fourth factor in the RANK/RANKL/OPG system for osteodastogenesis, which regulates OPG and RANK via direct interaction. (C) 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bone.2014.12.058

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CCN family protein 2 (CCN2) promotes the early differentiation, but inhibits the terminal differentiation of skeletal myoblasts Reviewed

Takashi Nishida, Satoshi Kubota, Eriko Aoyama, Danilo Janune, Karen M. Lyons, Masaharu Takigawa

JOURNAL OF BIOCHEMISTRY 157 ( 2 ) 91 - 100 2015.2

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Many studies have reported that CCN family protein 2 (also known as connective tissue growth factor) induces fibrotic response in skeletal muscle, thus emphasizing the pathological role of CCN2 in muscle tissues. However, the physiological role of CCN2 in myogenesis is still unknown. This study clarified the CCN2 functions during myogenesis. Recombinant CCN2 (rCCN2) promoted proliferation and MyoD production in C2C12 cells and primary myoblasts, but inhibited myogenin production. In accordance with these findings, the gene expression levels of myosin heavy chain, which is a marker of terminally differentiated myoblasts and desmin, which is the main intermediate filament protein of muscle cells, were decreased by rCCN2 treatment. In vivo analyses with Ccn2-deficient skeletal muscle revealed decreased proliferating cell nuclear antigen (PCNA)/MyoD double positive cells and muscle hypoplasia. Consistent with this finding, myogenic marker genes and myotube formation were repressed in Ccn2-deficient myoblasts. The protein production of CCN2 was increased in C2C12 myoblasts treated with tumor necrosis factor-alpha, which is a pro-inflammatory cytokine, suggesting its role in muscle regeneration after inflammation. These findings indicate that CCN2 promotes proliferation and early differentiation but inhibits the terminal differentiation of myoblasts, thus suggesting that CCN2 plays a physiological role in myogenesis.

DOI： 10.1093/jb/mvu056

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Cellular and molecular actions of CCN2/CTGF and its role under physiological and pathological conditions

Satoshi Kubota, Masaharu Takigawa

CLINICAL SCIENCE 128 ( 3 ) 181 - 196 2015.2

Language：English Publisher：PORTLAND PRESS LTD

CCN family protein 2 (CCN2), also widely known as connective tissue growth factor (CTGF), is one of the founding members of the CCN family of matricellular proteins. Extensive investigation on CCN2 over decades has revealed the novel molecular action and functional properties of this unique signalling modulator. By its interaction with multiple molecular counterparts, CCN2 yields highly diverse and context-dependent biological outcomes in a variety of microenvironments. Nowadays, CCN2 is recognized to conduct the harmonized development of relevant tissues, such as cartilage and bone, in the skeletal system, by manipulating extracellular signalling molecules involved therein by acting as a hub through a web. However, on the other hand, CCN2 occasionally plays profound roles in major human biological disorders, including fibrosis and malignancies in major organs and tissues, by modulating the actions of key molecules involved in these clinical entities. In this review, the physiological and pathological roles of this unique protein are comprehensively summarized from a molecular network-based viewpoint of CCN2 functionalities.

DOI： 10.1042/CS20140264

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New functional aspects of CCN2 revealed by trans-omic approaches Reviewed

Kubota, S, Maeda-Uematsu, A, Nishida, T, Takigawa, M

Journal of Oral Biosciences 57 37 - 43 2015

Role of CCN2 in Amino Acid Metabolism of Chondrocytes.

Murase Y, Hattori T, Aoyama E, Nishida T, Maeda-Uematsu A, Kawaki H, Lyons KM, Sasaki A, Takigawa M, Kubota S

J Cell Biochem 151 - 155 2015

Fluocinolone Acetonide Is a Potent Synergistic Factor of TGF-beta 3-Associated Chondrogenesis of Bone Marrow-Derived Mesenchymal Stem Cells for Articular Surface Regeneration Reviewed

Hara, Emilio Satoshi, Ono, Mitsuaki, Hai Thanh Pham, Sonoyama, Wataru, Kubota, Satoshi, Takigawa, Masaharu, Matsumoto, Takuya, Young, Marian F., Olsen, Bjorn R., Kuboki, Takuo

Journal of Bone and Mineral Research 30 ( 9 ) 1585 - 1596 2015

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

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

SURGERY 156 ( 3 ) 548 - 555 2014.9

Language：English Publishing type：Research paper (scientific journal) Publisher：MOSBY-ELSEVIER

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.

DOI： 10.1016/j.surg.2014.04.014

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Direct interaction between CCN family protein 2 and fibroblast growth factor 1

Tarek Abd El Kader, Satoshi Kubota, Ken Anno, Saho Tanaka, Takashi Nishida, Takayuki Furumatsu, Eriko Aoyama, Takuo Kuboki, Masaharu Takigawa

JOURNAL OF CELL COMMUNICATION AND SIGNALING 8 ( 2 ) 157 - 163 2014.6

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

In an attempt to find out a new molecular counterpart of CCN family protein 2 (CCN2), a matricellular protein with multiple functions, we performed an interactome analysis and found fibroblast growth factor (FGF) -1 as one of the candidates. Solid-phase binding assay indicated specific binding between CCN2 and FGF-1. This binding was also confirmed by surface plasmon resonance (SPR) analysis that revealed a dissociation constant (Kd) of 3.98 nM indicating strong molecular interaction between the two. RNA analysis suggested that both FGF-1 and CCN2 could be produced by chondrocytes and thus their interaction in the cartilage is possible. These findings for the first time indicate the direct interaction of CCN2 and FGF-1 and suggest the co-presence of these molecules in the cartilage microenvironment. CCN2 is a well-known promoter of cartilage development and regeneration, whereas the physiological and pathological role of FGF-1 in cartilage mostly remains unclear. Biological role of FGF-1 itself in cartilage is also suspected.

DOI： 10.1007/s12079-014-0232-z

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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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

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.

DOI： 10.1007/s12079-014-0220-3

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CCN2 as a novel molecule supporting energy metabolism of chondrocytes. Reviewed

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

Journal of cellular biochemistry 115 ( 5 ) 854 - 865 2014.5

Differential Expression of Vascular Endothelial Growth Factor in High- and Low-Metastasis Cell Lines of Salivary Gland Adenoid Cystic Carcinoma Reviewed

Seiji Kondo, Yoshiki Mukudai, Daisuke Soga, Takashi Nishida, Masaharu Takigawa, Tatsuo Shirota

ANTICANCER RESEARCH 34 ( 2 ) 671 - 677 2014.2

Language：English Publishing type：Research paper (scientific journal) Publisher：INT INST ANTICANCER RESEARCH

We used high- (ACCM) and low- (ACC2) metastasis cell lines of human adenoid cystic carcinoma (ACC) as an experimental model to study metastatic mechanisms and compare their expression levels for angiogenic-related factor vascular endothelial growth factor (VEGF). By using a series of extensive analyses, hypoxia-inducible factor-1 (HIF-1) alpha-dependent VEGF expression levels were observed to be higher in ACCM cell lines, increasing the possible development of tumor metastasis, compared to ACC2 cell lines. Our findings provide the novel insight that HIF-1 alpha-dependent VEGF overexpression under hypoxic conditions shows to some extent associations with the metastatic tendency of ACC cells and may function as a potential target for ACC therapy.

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Dexamethasone differentially regulates Bcl-2 family proteins in human proliferative chondrocytes: Role of pro-apoptotic Bid Reviewed

Farasat Zaman, Dionisios Chrysis, Kirsten Huntjens, Andrei Chagin, Masaharu Takigawa, Bengt Fadeel, Lars Savendahl

TOXICOLOGY LETTERS 224 ( 2 ) 196 - 200 2014.1

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Glucocorticoids (GCs) are widely used to treat inflammatory diseases and cancers. A multitude of undesired side effects have been reported in GC-treated patients including decreased linear bone growth. We have previously reported that GCs activate the caspase cascade and trigger Bax-mediated mitochondrial apoptosis in growth plate chondrocytes causing growth retardation in young mice. To further explore the role of mitochondrial apoptosis in GC-induced bone growth retardation, a number of pro- and anti-apoptotic proteins were studied in ex vivo cultures of human growth plate cartilage and human HCS-2/8 proliferative chondrocytes exposed to dexamethasone. Dexamethasone was found to increase the pro-apoptotic proteins Bcl-xS, Bad, and Bak as well as the proteolysis of Bid. Anti-Bid small interfering RNA partially rescued the chondrocytes from dexamethasone-induced apoptosis. Taken together, our data suggest that GC treatment differentially regulates Bcl-2 family member proteins to facilitate mitochondrial apoptosis in proliferative chondrocytes thereby contributing to GC-induced bone growth impairment. Prevention of this imbalance between pro- and anti-apoptotic Bcl-2 family proteins may provide a new strategy to protect from adverse effects of GCs on bone growth. (C) 2013 The Authors. Published by Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.toxlet.2013.10.020

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