Updated on 2024/05/09

写真a

 
Wang Ziyi
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Special-Appointment Assistant Professor
Position
Special-Appointment Assistant Professor
External link

Degree

  • Doctor of Philosophy in Dental Science ( 2020.9   Okayama University )

Research Interests

  • Bone metabolism

  • Bioinformatics

Research Areas

  • Life Science / Regenerative dentistry and dental engineering  / Regenerative dentistry and dental engineering: Orthodontics

  • Life Science / Developmental dentistry  / Developmental dentistry: Cleft lip/palate

Education

  • Okayama University   大学院医歯薬学総合研究科   機能再生・再建科学専攻

    2016.10 - 2020.9

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    Country: Japan

    Notes: 歯科矯正学分野

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  • Dalian Medical University   Graduate School of Dalian Medical University   Dental School

    2014.9 - 2016.6

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    Country: China

    Notes: Orthodontics

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  • Foshan University   Dental School   Dentistry

    2008.9 - 2013.6

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    Country: China

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Research History

  • Japan Society for the Promotion of Science (JSPS)   Postdoctoral Fellowships   PD

    2022.4 - 2024.3

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    Country:Japan

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  • Indiana University–Purdue University   Indiana Center for Musculoskeletal Health   Visiting Faculty

    2019.5 - 2019.10

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    Country:United States

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  • Japan Society for the Promotion of Science (JSPS)   Research Fellowship   DC2

    2019.4 - 2021.3

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    Country:Japan

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  • Okayama University   Department of Orthodontics   Short-term International Student   O-NECUS

    2014.10 - 2015.5

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    Country:Japan

    Notes:岡山大学-中国東北部大学院留学生交流プログラム O-NECUS短期留学制度

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  • Okayama University   Molecular Biology and Biochemistry, Faculty of Medicine, Dentistry and Pharmaceutical Sciences   Research Assistant Professor

    2024.4

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    Country:Japan

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  • Okayama University   Department of Oral Rehabilitation and Regenerative Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences   Technician

    2021.8 - 2022.3

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    Country:Japan

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  • Okayama University   Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences   Part-time Researcher

    2021.4 - 2021.7

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    Country:Japan

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Professional Memberships

  • The American Society for Bone and Mineral Research (ASBMR)

    2017.6

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  • Japanese Cleft Palate Association

    2022.5 - 2023.5

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  • International Society of Bone Morphometry

    2019.7 - 2020.7

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  • Japanese Orthodontic Society

    2018.10 - 2020.10

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  • Japanese Society For Bone Morphometry

    2018.6 - 2019.6

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  • Japanese Association for Oral Biology

    2017.9 - 2018.9

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  • Japanese Society for Bone and Mineral Research

    2017.7 - 2019.7

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  • Chinese Stomatological Association

    2015 - 2017

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Papers

  • Filamin A mediates embryonical palatal fusion by linking mechanotransduction with β-Catenin/Smad2 International coauthorship

    Ziyi Wang, Satoru Hayano, Yao Weng, Xindi Mu, Mitsuaki Ono, Jeremie Oliver Piña, Rena N. D'Souza, Takashi Yamashiro, Toshitaka Oohashi, Hiroshi Kamioka

    bioRxiv   2024.2

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Cold Spring Harbor Laboratory  

    To decipher potential mechanisms underlying cleft palate (CP), we used advanced bioinformatic integrated with literature mining and genome-wide association study (GWAS). Re-analysis of RNA-seq data (GSE45568, GSE185279) combined with literature mining highlighted the roles of Filamin A (Flna) and Epithelial-Mesenchymal Transition (EMT) in palatal development. Immunofluorescence of in vivo palatal shelves showed increased Flna in medial edge epithelial (MEE) cells and EMT cells located in an epithelial triangle. Inhibition of TGF-β or RhoA and mechanical stimuli impacted Flna expression in ex vivo cultured palatal shelves. Re-analysis of scRNA-seq data (GSE155928) highlighted a correlation between Flna and Ctnnb1 in EMT cells. Flna knockdown affected β-catenin/Smad2 expression in cultured palatal shelves and HaCaT cells. Epithelium-specific knockout of Flna delayed palatal fusion in female mice but not males. Mendelian randomization analysis suggested that parental habitual physical activity (HPA) was causally associated with lower risk of CP in their offspring. Together, these findings suggested that parental HPA could benefit their offspring's palatal development through Flna by linking mechanotransduction with the Wnt/TGF-β/Smad signaling pathways during palatal fusion.

    DOI: 10.1101/2024.02.16.580664

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  • Loading history changes the morphology and compressive force-induced expression of receptor activator of nuclear factor kappa B ligand/osteoprotegerin in MLO-Y4 osteocytes Reviewed International journal

    Ziyi Wang, Yao Weng, Yoshihito Ishihara, Naoya Odagaki, Ei Ei Hsu Hlaing, Takashi Izawa, Hirohiko Okamura, Hiroshi Kamioka

    PeerJ   8   2020.11

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:PeerJ  

    Abstract

    Background
    In this study, we investigated the effect of the mechanical loading history on the expression of receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) in MLO-Y4 osteocyte-like cells.

    Methods
    Three hours after MLO-Y4 osteocytes were seeded, a continuous compressive force (CCF) of 31 dynes/cm2 with or without additional CCF (32 dynes/cm2) was loaded onto the osteocytes. After 36 h, the additional CCF (loading history) was removed for a recovery period of 10 h. The expression of RANKL, OPG, RANKL/OPG ratio, cell numbers, viability and morphology were time-dependently examined at 0, 3, 6 and 10 h. Then, the same additional CCF was applied again for 1 h to all osteocytes with or without the gap junction inhibitor to examine the expression of RANKL, OPG, the RANKL/OPG ratio and other genes that essential to characterize the phenotype of MLO-Y4 cells. Fluorescence recovery after photobleaching technique was also applied to test the differences of gap-junctional intercellular communications (GJIC) among MLO-Y4 cells.

    Results
    The expression of RANKL and OPG by MLO-Y4 osteocytes without a loading history was dramatically decreased and increased, respectively, in response to the 1-h loading of additional weight. However, the expression of RANKL, OPG and the RANKL/OPG ratio were maintained at the same level as in the control group in the MLO-Y4 osteocytes with a loading history but without gap junction inhibitor treatment. Treatment of loading history significantly changed the capacity of GJIC and protein expression of connexin 43 (Cx43) but not the mRNA expression of Cx43. No significant difference was observed in the cell number or viability between the MLO-Y4 osteocyte-like cells with and without a loading history or among different time checkpoints during the recovery period. The cell morphology showed significant changes and was correlated with the expression of OPG, Gja1 and Dmp1 during the recovery period.

    Conclusion
    Our findings indicated that the compressive force-induced changes in the RANKL/OPG expression could be habituated within at least 11 h by 36-h CCF exposure. GJIC and cell morphology may play roles in response to loading history in MLO-Y4 osteocyte-like cells.

    DOI: 10.7717/peerj.10244

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  • Changes in the intra- and peri-cellular sclerostin distribution in lacuno-canalicular system induced by mechanical unloading Reviewed International journal

    Ryuta Osumi, Ziyi Wang, Yoshihito Ishihara, Naoya Odagaki, Tadahiro Iimura, Hiroshi Kamioka

    Journal of Bone and Mineral Metabolism   39 ( 2 )   148 - 159   2020.8

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    Abstract
    Introduction
    Mechanical stimuli regulate Sclerostin (Scl), a negative regulator of bone formation, expression in osteocytes. However, the detailed Scl distribution in osteocytes in response to mechanical unloading remains unclear.

    Materials and methods
    Twelve-week-old male rats were used. The sciatic and femoral nerves on the right side were excised as mechanical unloading treatment. A sham operation was performed on the left side. One week after neurotrauma, the bone density of the femora was evaluated by peripheral quantitative computed tomography, and immunofluorescence was performed in coronal sections of the femoral diaphysis. The mean fluorescence intensity and fluorescent profile of Scl from the marrow to the periosteal side were analyzed to estimate the Scl expression and determine to which side (marrow or periosteal) the Scl prefers to distribute in response to mechanical unloading. The most sensitive region indicated by the immunofluorescence results was further investigated by transmission electron microscopy (TEM) with immunogold staining to show the Scl expression changes in different subcellular structures.

    Results
    In femur distal metaphysis, neurotrauma-induced mechanical unloading significantly decreased the bone density, made the distribution of Scl closer to the marrow on the anterior and medial side, and increased the Scl expression only on the lateral side. TEM findings showed that only the expression of Scl in canaliculi was increased by mechanical unloading.

    Conclusions
    Our results showed that even short-term mechanical unloading is enough to decrease bone density, and mechanical unloading not only regulated the Scl expression but also changed the Scl distribution in both the osteocyte network and subcellular structures.

    DOI: 10.1007/s00774-020-01135-9

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    Other Link: https://link.springer.com/article/10.1007/s00774-020-01135-9/fulltext.html

  • Screening of key candidate genes and pathways for osteocytes involved in the differential response to different types of mechanical stimulation using a bioinformatics analysis Reviewed International journal

    Ziyi Wang, Yoshihito Ishihara, Takanori Ishikawa, Mitsuhiro Hoshijima, Naoya Odagaki, Ei Ei Hsu Hlaing, Hiroshi Kamioka

    Journal of Bone and Mineral Metabolism   37 ( 4 )   614 - 626   2019.7

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    Abstract
    This study aimed to predict the key genes and pathways that are activated when different types of mechanical loading are applied to osteocytes. mRNA expression datasets (series number of GSE62128 and GSE42874) were obtained from Gene Expression Omnibus database (GEO). High gravity-treated osteocytic MLO-Y4 cell-line samples from GSE62128 (Set1), and fluid flow-treated MLO-Y4 samples from GSE42874 (Set2) were employed. After identifying the differentially expressed genes (DEGs), functional enrichment was performed. The common DEGs between Set1 and Set2 were considered as key DEGs, then a protein–protein interaction (PPI) network was constructed using the minimal nodes from all of the DEGs in Set1 and Set2, which linked most of the key DEGs. Several open source software programs were employed to process and analyze the original data. The bioinformatic results and the biological meaning were validated by in vitro experiments. High gravity and fluid flow induced opposite expression trends in the key DEGs. The hypoxia-related biological process and signaling pathway were the common functional enrichment terms among the DEGs from Set1, Set2 and the PPI network. The expression of almost all the key DEGs (Pdk1, Ccng2, Eno2, Egln1, Higd1a, Slc5a3 and Mxi1) were mechano-sensitive. Eno2 was identified as the hub gene in the PPI network. Eno2 knockdown results in expression changes of some other key DEGs (Pdk1, Mxi1 and Higd1a). Our findings indicated that the hypoxia response might have an important role in the differential responses of osteocytes to the different types of mechanical force.

    DOI: 10.1007/s00774-018-0963-7

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    Other Link: http://link.springer.com/article/10.1007/s00774-018-0963-7/fulltext.html

  • The temporospatial pattern of energy metabolism coordinates the interactions between the bones and other organ systems Invited Reviewed International journal

    Ziyi Wang, Hiroshi Kamioka

    Journal of Oral Biosciences   60 ( 1 )   8 - 14   2018.3

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Elsevier {BV}  

    Abstract
    Background: Bones adapt to loads by changing their structure. This biomechanical interaction and the formation/maintenance of bones are orchestrated by three major cell types residing in the bones: osteoblasts, osteocytes, and osteoclasts. Recent findings suggest that, in addition to their biomechanical interactions, bones and other organ systems may also communicate biochemically. Highlight: This brief review will discuss the interaction between the bones and the nervous system, vasculature, muscle, and fat tissues, with an emphasis on the role of the energy metabolism in these interactions. Conclusion: Studies on the connections between bones and other organ systems indicate the possible existence of a temporospatial pattern of energy metabolism through the cellular biorhythm and migration. © 2017 Japanese Association for Oral Biology

    DOI: 10.1016/j.job.2017.11.001

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  • Alternation in the gap-junctional intercellular communication capacity during the maturation of osteocytes in the embryonic chick calvaria Reviewed International journal

    Ziyi Wang, Naoya Odagaki, Tomoyo Tanaka, Mana Hashimoto, Masahiro Nakamura, Satoru Hayano, Yoshihito Ishihara, Noriaki Kawanabe, Hiroshi Kamioka

    Bone   91   20 - 29   2016.10

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Elsevier {BV}  

    Abstract
    Introduction: The intercellular network of cell-cell communication among osteocytes is mediated by gap junctions. Gap junctional intercellular communication (GJIC) is thought to play an important role in the integration and synchronization of bone remodeling. To further understand the mechanism of bone development it is important to quantify the difference in the GJIC capacity of young and developmentally mature osteocytes.

    Materials and methods: We first established an embryonic chick calvaria growth model to show the growth of the calvaria in embryos at 13 to 21days of age. We then applied a fluorescence recovery after photobleaching (FRAP) technique to compare the difference in the GJIC capacity of young osteocytes with that of developmentally mature osteocytes. Finally, we quantified the dye (Calcein) diffusion from the FRAP data using a mathematic model of simple diffusion which was also used to identify simple diffusion GJIC pattern cells (fitted model) and accelerated diffusion GJIC pattern cells (non-fitted model).

    Results: The relationship between the longest medial-lateral length of the calvaria (frontal bone) and the embryonic age fit a logarithmic growth model: length=5.144×ln(day)-11.340. The morphometric data during osteocyte differentiation showed that the cellular body becomes more spindle-shaped and that the cell body volume decreased by approximately 22% with an increase in the length of the processes between the cells. However, there were no significant differences in the cellular body surface area or in the distance between the mass centres of the cells. The dye-displacement rate in young osteocytes was significantly higher than that in developmentally mature osteocytes: dye displacement only occurred in 26.88% of the developmentally mature osteocytes, while it occurred in 64.38% of the young osteocytes. Additionally, in all recovered osteocytes, 36% of the developmentally mature osteocytes comprised non-fitted model cells while 53.19% of the young osteocytes were the non-fitted model, which indicates the active transduction of dye molecules. However, there were no statistically significant differences between the young and developmentally mature osteocytes with regard to the diffusion coefficient, permeability coefficient, or permeance of the osteocyte processes, which were 3.93±3.77 (×10(-8)cm(2)/s), 5.12±4.56 (×10(-5)cm(2)/s) and 2.99±2.47 (×10(-13)cm(2)/s) (mean±SD), respectively.

    Conclusions: These experiments comprehensively quantified the GJIC capacity in the embryonic chick calvaria and indicated that the cell-cell communication capacity of the osteocytes in the embryonic chick calvaria was related to their development.

    Keywords: Connexins; Fluorescence recovery after photobleaching; Gap-junctional intercellular communication; Mathematic model of simple diffusion; Osteocyte transformation; Osteocytes.

    DOI: 10.1016/j.bone.2016.06.016

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  • Loss-of-function OGFRL1 variants identified in autosomal recessive cherubism families Reviewed International coauthorship International journal

    Mizuho Kittaka, Noriyoshi Mizuno, Hiroyuki Morino, Tetsuya Yoshimoto, Tianli Zhu, Sheng Liu, Ziyi Wang, Kotoe Mayahara, Kyohei Iio, Kaori Kondo, Toshio Kondo, Tatsuhide Hayashi, Sarah Coghlan, Yayoi Teno, Andrew Anh Phung Doan, Marcus Levitan, Roy B Choi, Shinji Matsuda, Kazuhisa Ouhara, Jun Wan, Annelise M Cassidy, Stephane Pelletier, Sheela Nampoothiri, Andoni J Urtizbera, Alexander G Robling, Mitsuaki Ono, Hideshi Kawakami, Ernst J Reichenberger, Yasuyoshi Ueki

    JBMR Plus   8 ( 6 )   ziae050   2024.4

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Oxford University Press (OUP)  

    Cherubism (OMIM 118400) is a rare craniofacial disorder in children characterized by destructive jawbone expansion due to the growth of inflammatory fibrous lesions. Our previous studies have shown that gain-of-function mutations in SH3 domain-binding protein 2 (SH3BP2) are responsible for cherubism and that a knock-in mouse model for cherubism recapitulates the features of cherubism, such as increased osteoclast formation and jawbone destruction. To date, SH3BP2 is the only gene identified to be responsible for cherubism. Since not all patients clinically diagnosed with cherubism had mutations in SH3BP2, we hypothesized that there may be novel cherubism genes and that these genes may play a role in jawbone homeostasis. Here, using whole exome sequencing, we identified homozygous loss-of-function variants in the opioid growth factor receptor like 1 (OGFRL1) gene in two independent autosomal recessive cherubism families from Syria and India. The newly identified pathogenic homozygous variants were not reported in any variant databases, suggesting that OGFRL1 is a novel gene responsible for cherubism. Single cell analysis of mouse jawbone tissue revealed that Ogfrl1 is highly expressed in myeloid lineage cells. We generated OGFRL1 knockout mice and mice carrying the Syrian frameshift mutation to understand the in vivo role of OGFRL1. However, neither mouse model recapitulated human cherubism or the phenotypes exhibited by SH3BP2 cherubism mice under physiological and periodontitis conditions. Unlike bone marrow-derived M-CSF-dependent macrophages (BMMs) carrying the SH3BP2 cherubism mutation, BMMs lacking OGFRL1 or carrying the Syrian mutation showed no difference in TNF-ɑ mRNA induction by LPS or TNF-ɑ compared to wild-type BMMs. Osteoclast formation induced by receptor activator of NF-κB ligand (RANKL) was also comparable. These results suggest that the loss-of-function effects of OGFRL1 in humans differ from those in mice and highlight the fact that mice are not always an ideal model for studying rare craniofacial bone disorders.

    DOI: 10.1093/jbmrpl/ziae050

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  • Antitumor activity of α‐pinene in T‐cell tumors Reviewed

    Masaya Abe, Noboru Asada, Maiko Kimura, Chie Fukui, Daisuke Yamada, Ziyi Wang, Masayuki Miyake, Takeshi Takarada, Mitsuaki Ono, Michinori Aoe, Wataru Kitamura, Masayuki Matsuda, Takashi Moriyama, Akifumi Matsumura, Yoshinobu Maeda

    Cancer Science   2024.1

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

    Abstract

    T‐cell acute leukemia and lymphoma have a poor prognosis. Although new therapeutic agents have been developed, their therapeutic effects are suboptimal. α‐Pinene, a monoterpene compound, has an antitumor effect on solid tumors; however, few comprehensive investigations have been conducted on its impact on hematologic malignancies. This report provides a comprehensive analysis of the potential benefits of using α‐pinene as an antitumor agent for the treatment of T‐cell tumors. We found that α‐pinene inhibited the proliferation of hematologic malignancies, especially in T‐cell tumor cell lines EL‐4 and Molt‐4, induced mitochondrial dysfunction and reactive oxygen species accumulation, and inhibited NF‐κB p65 translocation into the nucleus, leading to robust apoptosis in EL‐4 cells. Collectively, these findings suggest that α‐pinene has potential as a therapeutic agent for T‐cell malignancies, and further investigation is warranted.

    DOI: 10.1111/cas.16086

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  • Ruxolitinib altered IFN-β induced necroptosis of human dental pulp stem cells during osteoblast differentiation Reviewed

    Atsuko Tanaka, Satoru Hayano, Masayo Nagata, Takahiro Kosami, Ziyi Wang, Hiroshi Kamioka

    Archives of Oral Biology   155   105797   2023.11

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    DOI: 10.1016/j.archoralbio.2023.105797

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  • Lgr5-expressing secretory cells form a Wnt inhibitory niche in cartilage critical for chondrocyte identity Reviewed

    Angela Ruscitto, Peng Chen, Ikue Tosa, Ziyi Wang, Gan Zhou, Ingrid Safina, Ran Wei, Mallory M. Morel, Alia Koch, Michael Forman, Gwendolyn Reeve, Michael K. Lecholop, Marshall Wilson, Daniel Bonthius, Mo Chen, Mitsuaki Ono, Timothy C. Wang, Hai Yao, Mildred Embree

    Cell Stem Cell   30 ( 9 )   1179 - 1198   2023.9

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    DOI: 10.1016/j.stem.2023.08.004

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  • Neuropilin 1 (NRP1) Positively Regulates Adipogenic Differentiation in C3H10T1/2 Cells Reviewed

    Yaqiong Yu, Yoko Uchida-Fukuhara, Yao Weng, Yuhan He, Mika Ikegame, Ziyi Wang, Kaya Yoshida, Hirohiko Okamura, Lihong Qiu

    International Journal of Molecular Sciences   24 ( 8 )   7394   2023.4

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    DOI: 10.3390/ijms24087394

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  • Bulk RNA‐seq analyses of mandibular condylar cartilage in a post‐traumatic TMJ osteoarthritis rabbit model Reviewed International coauthorship International journal

    Ikue Tosa, Angela Ruscitto, Ziyi Wang, Kira Z. Chen, Mitsuaki Ono, Mildred C. Embree

    Orthodontics & Craniofacial Research   26 ( S1 )   131 - 141   2023.3

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

    Abstract

    Objective

    The temporomandibular joint (TMJ) is anatomically comprised of the mandibular condylar cartilage (CC) lined with fibrocartilaginous superficial zone and is crucial for eating and dental occlusion. TMJ osteoarthritis (OA) leads to pain, joint dysfunction and permanent loss of cartilage tissue. However, there are no drugs clinically available that ameliorate OA and little is known about global profiles of genes that contribute to TMJ OA. Furthermore, animal models that recapitulate the complexity of signalling pathways contributing to OA pathogenesis are crucial for designing novel biologics that thwart OA progression. We have previously developed a New Zealand white rabbit TMJ injury model that demonstrates CC degeneration. Here, we performed genome‐wide profiling to identify new signalling pathways critical for cellular functions during OA pathology.

    Materials and Methods

    Temporomandibular joint OA was surgically induced in New Zealand white rabbits. Three months following injury, we performed global gene expression profiling of the TMJ condyle. RNA samples from TMJ condyles were subjected to sequencing. After raw RNA‐seq data were mapped to relevant genomes, differential expression was analysed with DESeq2. Gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted.

    Results/Conclusions

    Our study revealed multiple pathways altered during TMJ OA induction including the Wnt, Notch and PI3K‐Akt signalling pathways. We demonstrate an animal model that recapitulates the complexity of the cues and signals underlying TMJ OA pathogenesis, which is essential for developing and testing novel pharmacologic agents to treat OA.

    DOI: 10.1111/ocr.12649

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  • SOD3 Expression in Tumor Stroma Provides the Tumor Vessel Maturity in Oral Squamous Cell Carcinoma Reviewed International journal

    May Wathone Oo, Hotaka Kawai, Htoo Shwe Eain, Yamin Soe, Kiyofumi Takabatake, Sho Sanou, Qiusheng Shan, Yasunori Inada, Masae Fujii, Yoko Fukuhara, Ziyi Wang, Shintaro Sukegawa, Mitsuaki Ono, Keisuke Nakano, Hitoshi Nagatsuka

    Biomedicines   10 ( 11 )   2729 - 2729   2022.10

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

    Tumor angiogenesis is one of the hallmarks of solid tumor development. The progressive tumor cells produce the angiogenic factors and promote tumor angiogenesis. However, how the tumor stromal cells influence tumor vascularization is still unclear. In the present study, we evaluated the effects of oral squamous cell carcinoma (OSCC) stromal cells on tumor vascularization. The tumor stromal cells were isolated from two OSCC patients with different subtypes: low invasive verrucous squamous carcinoma (VSCC) and highly invasive squamous cell carcinoma (SCC) and co-xenografted with the human OSCC cell line (HSC-2) on nude mice. In comparison, the CD34+ vessels in HSC-2+VSCC were larger than in HSC-2+SCC. Interestingly, the vessels in the HSC-2+VSCC expressed vascular endothelial cadherin (VE-cadherin), indicating well-formed vascularization. Our microarray data revealed that the expression of extracellular superoxide dismutase, SOD3 mRNA is higher in VSCC stromal cells than in SCC stromal cells. Moreover, we observed that SOD3 colocalized with VE-cadherin on endothelial cells of low invasive stroma xenograft. These data suggested that SOD3 expression in stromal cells may potentially regulate tumor vascularization in OSCC. Thus, our study suggests the potential interest in SOD3-related vascular integrity for a better OSCC therapeutic strategy.

    DOI: 10.3390/biomedicines10112729

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  • Treatment of Marmoset Intracerebral Hemorrhage with Humanized Anti-HMGB1 mAb Reviewed

    Dengli Wang, Daiki Ousaka, Handong Qiao, Ziyi Wang, Kun Zhao, Shangze Gao, Keyue Liu, Kiyoshi Teshigawara, Kenzo Takada, Masahiro Nishibori

    Cells   11 ( 19 )   2970   2022.9

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    DOI: 10.3390/cells11192970

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  • A morphometric analysis of the osteocyte canaliculus using applied automatic semantic segmentation by machine learning Reviewed

    Tabata, K., Hashimoto, M., Takahashi, H., Wang, Z., Nagaoka, N., Hara, T., Kamioka, H.

    Journal of Bone and Mineral Metabolism   40 ( 4 )   2022

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

    DOI: 10.1007/s00774-022-01321-x

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  • Roles for B[a]P and FICZ in subchondral bone metabolism and experimental temporomandibular joint osteoarthritis via the AhR/Cyp1a1 signaling axis Reviewed

    Yuri Yoshikawa, Takashi Izawa, Yusaku Hamada, Hiroko Takenaga, Ziyi Wang, Naozumi Ishimaru, Hiroshi Kamioka

    Scientific Reports   11 ( 1 )   2021.12

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media {LLC}  

    <jats:title>Abstract</jats:title><jats:p>Bone loss due to smoking represents a major risk factor for fractures and bone osteoporosis. Signaling through the aryl hydrocarbon receptor (AhR) and its ligands contributes to both bone homeostasis and inflammatory diseases. It remains unclear whether the same AhR signaling axis affects the temporomandibular joint (TMJ). The aim of this study was to investigate possible mechanisms which mediate bone loss in the TMJ due to smoking. In particular, whether benzo[<jats:italic>a</jats:italic>]pyrene (B[<jats:italic>a</jats:italic>]P), a carcinogen of tobacco smoke, induces expression of the AhR target gene, Cyp1a1, in mandibular condyles. Possible functions of an endogenous ligand of FICZ, were also investigated in a TMJ-osteoarthritis (OA) mouse model. B[<jats:italic>a</jats:italic>]P was administered orally to wild-type and <jats:italic>AhR</jats:italic><jats:sup>−/−</jats:sup> mice and bone metabolism was subsequently examined. TMJ-OA was induced in wild-type mice with forceful opening of the mouth. Therapeutic functions of FICZ were detected with μCT and histology. Exposure to B[<jats:italic>a</jats:italic>]P accelerated bone loss in the mandibular subchondral bone. This bone loss manifested with osteoclastic bone resorption and upregulated expression of Cyp1a1 in an <jats:italic>AhR</jats:italic>-dependent manner. In a mouse model of TMJ-OA, FICZ exhibited a dose-dependent rescue of mandibular subchondral bone loss by repressing osteoclast activity. Meanwhile, in vitro, pre-treatment with FICZ reduced RANKL-mediated osteoclastogenesis. B[<jats:italic>a</jats:italic>]P regulates mandibular subchondral bone metabolism via the Cyp1a1. The AhR ligand, FICZ, can prevent TMJ-OA by regulating osteoclast differentiation.</jats:p>

    DOI: 10.1038/s41598-021-94470-4

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  • Endonuclease increases efficiency of osteoblast isolation from murine calvariae Reviewed International coauthorship International journal

    Yosuke Asano, Yoshinori Matsumoto, Jose La Rose, Fang He, Takayuki Katsuyama, Wang Ziyi, Shigetomo Tsuji, Hiroshi Kamioka, Robert Rottapel, Jun Wada

    Scientific Reports   11 ( 1 )   2021.12

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media {LLC}  

    Abstract:
    Bone is a highly dynamic organ that undergoes remodeling equally regulated by osteoblast-mediated bone formation and osteoclast-mediated bone resorption. To clarify the regulation of osteoblastogenesis, primary murine osteoblasts are required for an in vitro study. Primary osteoblasts are isolated from neonatal calvariae through digestion with collagenase. However, the number of cells collected from one pup is not sufficient for further in vitro experiments, leading to an increase in the use of euthanized pups. We hypothesized that the viscosity of digested calvariae and digestion solution supplemented with collagenase results in cell clumping and reduction of isolated cells from bones. We simply added Benzonase, a genetically engineered endonuclease that shears all forms of DNAs/RNAs, in order to reduce nucleic acid-mediated viscosity. We found that addition of Benzonase increased the number of collected osteoblasts by three fold compared to that without Benzonase through reduction of viscosity. Additionally, Benzonase has no effect on cellular identity and function. The new osteoblast isolation protocol with Benzonase minimizes the number of neonatal pups required for an in vitro study and expands the concept that isolation of other populations of cells including osteocytes that are difficult to be purified could be modified by Benzonase.

    DOI: 10.1038/s41598-021-87716-8

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  • Extracellular vesicles of P. gingivalis-infected macrophages induce lung injury Reviewed

    Kayo Yoshida, Kaya Yoshida, Natsumi Fujiwara, Mariko Seyama, Kisho Ono, Hotaka Kawai, Jiajie Guo, Ziyi Wang, Yao Weng, Yaqiong Yu, Yoko Uchida-Fukuhara, Mika Ikegame, Akira Sasaki, Hitoshi Nagatsuka, Hiroshi Kamioka, Hirohiko Okamura, Kazumi Ozaki

    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease   1867 ( 11 )   166236 - 166236   2021.11

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    DOI: 10.1016/j.bbadis.2021.166236

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  • Investigation of the molecular causes underlying physical abnormalities in Diamond‐Blackfan anemia patients with RPL5 haploinsufficiency Reviewed International journal

    Yuko Fukui, Satoru Hayano, Noriaki Kawanabe, Ziyi Wang, Akira Shimada, Megumu K. Saito, Isao Asaka, Hiroshi Kamioka

    Pathology International   71 ( 12 )   803 - 813   2021.9

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    Abstract

    Diamond‐Blackfan anemia (DBA) is a genetic disorder caused by mutations in genes encoding ribosomal proteins and characterized by erythroid aplasia and various physical abnormalities. Although accumulating evidence suggests that defective ribosome biogenesis leads to p53‐mediated apoptosis in erythroid progenitor cells, little is known regarding the underlying causes of the physical abnormalities. In this study, we established induced pluripotent stem cells from a DBA patient with RPL5 haploinsufficiency. These cells retained the ability to differentiate into osteoblasts and chondrocytes. However, RPL5 haploinsufficiency impaired the production of mucins and increased apoptosis in differentiated chondrocytes. Increased expression of the pro‐apoptotic genes BAX and CASP9 further indicated that RPL5 haploinsufficiency triggered p53‐mediated apoptosis in chondrocytes. Murine double minute 2 (MDM2), the primary negative regulator of p53, plays a crucial role in erythroid aplasia in DBA patient. We found the phosphorylation level of MDM2 was significantly decreased in RPL5 haploinsufficient chondrocytes. In stark contrast, we found no evidence that RPL5 haploinsufficiency impaired osteogenesis. Collectively, our data support a model in which RPL5 haploinsufficiency specifically induces p53‐mediated apoptosis in chondrocytes through MDM2 inhibition, which leads to physical abnormalities in DBA patients.

    DOI: 10.1111/pin.13168

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    Other Link: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/pin.13168

  • O-GlcNAcylation drives calcium signaling toward osteoblast differentiation: A bioinformatics-oriented study Reviewed

    Weng, Y., Wang, Z., Fukuhara, Y., Tanai, A., Ikegame, M., Yamada, D., Takarada, T., Izawa, T., Hayano, S., Yoshida, K., Kamioka, H., Okamura, H.

    BioFactors   47 ( 6 )   992 - 1015   2021

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    DOI: 10.1002/biof.1774

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  • The expression and regulation of Wnt1 in tooth movement–initiated mechanotransduction Reviewed International journal

    Ei Ei Hsu Hlaing, Yoshihito Ishihara, Naoya Odagaki, Ziyi Wang, Mika Ikegame, Hiroshi Kamioka

    American Journal of Orthodontics and Dentofacial Orthopedics   158 ( 6 )   e151 - e160   2020.12

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    Abstract
    Introduction: The Wnt signaling pathway acts as a key regulator of skeletal development and its homeostasis. However, the potential role of Wnt1 in the mechanotransduction machinery of orthodontic tooth movement-initiated bone remodeling is still unclear. Hence, this study focused on the regulatory dynamics of the Wnt1 expression in both the periodontal ligament (PDL) and osteocytes in vivo and in vitro.

    Methods: The Wnt1 expression in the orthodontically moved maxillary first molar in mice was assessed at 0, 1, and 5 days, on both the compression and tension sides. Primary isolated human PDL (hPDL) fibroblasts, as well as murine long-bone osteocyte-Y4 (MLO-Y4) cells, were exposed to continuous compressive force and static tensile force.

    Results: The relative quantification of immunodetection showed that orthodontic tooth movement significantly stimulated the Wnt1 expression in both the PDL and alveolar osteocytes on the tension side on day 5, whereas the expression on the compression side did not change. This increase in the Wnt1 expression, shown in vivo, was also noted after the application of 12% static tensile force in isolated hPDL fibroblasts and 20% in MLO-Y4 cells. In contrast, a compressive force led to the attenuation of the Wnt1 gene expression in both hPDL fibroblasts and MLO-Y4 cells in a force-dependent manner. In the osteocyte-PDL coculture system, recombinant sclerostin attenuated Wnt1 in PDL, whereas the antisclerostin antibody upregulated its gene expression, indicating that mechanically-driven Wnt1 signaling in PDL might be regulated by osteocytic sclerostin.

    Conclusions: Our findings provide that Wnt1 signaling plays a vital role in tooth movement-initiated bone remodeling via innovative mechanotransduction approaches.

    DOI: 10.1016/j.ajodo.2020.08.006

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  • N-(3-oxododecanoyl)-homoserine lactone regulates osteoblast apoptosis and differentiation by mediating intracellular calcium Reviewed International coauthorship International journal

    Jiajie Guo, Ziyi Wang, Yao Weng, Haoze Yuan, Kaya Yoshida, Mika Ikegame, Kenta Uchibe, Hiroshi Kamioka, Kazuhiko Ochiai, Hirohiko Okamura, Lihong Qiu

    Cellular Signalling   75   109740 - 109740   2020.11

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    Abstract
    Pseudomonas aeruginosa (P. aeruginosa) is associated with periapical periodontitis. The lesions are characterized by a disorder in osteoblast metabolism. Quorum sensing molecular N-(3-oxododecanoyl)-homoserine lactone (AHL) is secreted by P. aeruginosa and governs the expression of numerous virulence factors. AHL can trigger intracellular calcium ([Ca2+]i) fluctuations in many host cells. However, it is unclear whether AHL can regulate osteoblast metabolism by affecting [Ca2+]i changes or its spatial correlation. We explored AHL-induced apoptosis and differentiation in pre-osteoblastic MC3T3-E1 cells and evaluated [Ca2+]i mobilization using several extraction methods. The spatial distribution pattern of [Ca2+]i among cells was investigated by Moran's I, an index of spatial autocorrelation. We found that 30 μM and 50 μM AHL triggered opposing osteoblast fates. At 50 μM, AHL inhibited osteoblast differentiation by promoting mitochondrial-dependent apoptosis and negatively regulating osteogenic marker genes, including Runx2, Osterix, bone sialoprotein (Bsp), and osteocalcin (OCN). In contrast, prolonged treatment with 30 μM AHL promoted osteoblast differentiation concomitantly with cell apoptosis. The elevation of [Ca2+]i levels in osteoblasts treated with 50 μM AHL was spatially autocorrelated, while no such phenomenon was observed in 30 μM AHL-treated osteoblasts. The blocking of cell-to-cell spatial autocorrelation in the osteoblasts provoked by 50 μM AHL significantly inhibited apoptosis and partially restored differentiation. Our observations suggest that AHL affects the fate of osteoblasts (apoptosis and differentiation) by affecting the spatial correlation of [Ca2+]i changes. Thus, AHL acts as a double-edged sword for osteoblast function.

    Keywords: Apoptosis; Calcium; Differentiation; N-(3-oxododecanoyl)-homoserine lactone; Osteoblast metabolism; Spatial autocorrelation.

    DOI: 10.1016/j.cellsig.2020.109740

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  • Outer membrane vesicles derived from Porphyromonas gingivalis induced cell death with disruption of tight junctions in human lung epithelial cells Reviewed International journal

    Yuhan He, Noriko Shiotsu, Yoko Uchida-Fukuhara, Jiajie Guo, Yao Weng, Mika Ikegame, Ziyi Wang, Kisho Ono, Hiroshi Kamioka, Yasuhiro Torii, Akira Sasaki, Kaya Yoshida, Hirohiko Okamura

    Archives of Oral Biology   118   104841 - 104841   2020.10

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    Abstract
    Objective
    Porphyromonas gingivalis (P. gingivalis) is a major bacterium responsible for the progression of periodontitis. P. gingivalis produces small vesicles called outer membrane vesicles (OMVs) containing virulence factors. Increasing evidence suggests a close relationship between periodontitis and respiratory system diseases, such as aspiration pneumonia. However, little is known about whether P. gingivalis OMVs give rise to the impediment of lung epithelial cells. We investigated the effect of the OMVs on cell viability and tight junctions of lung epithelial cells.

    Design
    Human lung epithelial A549 cells were treated with P. gingivalis OMVs. Cell viability was evaluated, and cell morphology was examined using scanning electron and phase contrast microscopies. To detect apoptosis induced by P. gingivalis OMVs, activation of caspase-3 and poly ADP-ribose polymerase (PARP) cleavage was examined by using Western blotting. Immunocytochemistry was performed to stain tight junction proteins.

    Results
    P. gingivalis OMVs decreased cell viability in A549 cells in a dose- and time-dependent manner. Microscopic analysis revealed that the OMVs induced morphological changes leading to irregular cell membrane structures. The OMVs caused cell shrinkage, membrane blebbing, and cytoplasmic expulsion in a dose-dependent manner. Western blot analysis showed the OMVs induced caspase-3 activation and PARP cleavage. Treatment with the OMVs disrupted the intact distributions of tight junction proteins.

    Conclusions
    These results indicate that P. gingivalis OMVs induced cell death by destroying the barrier system in lung epithelial cells. Our present study raises the possibility that P. gingivalis OMVs is an important factor in the engagement of periodontitis with respiratory system diseases.

    DOI: 10.1016/j.archoralbio.2020.104841

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  • The Analysis of Gap Junctional Intercellular Communication Among Osteocytes in Chick Calvariae by Fluorescence Recovery After Photobleaching Invited Reviewed International journal

    Ziyi Wang, Yoshihito Ishihara, Hiroshi Kamioka

    Methods in Molecular Biology   215 - 223   2020.9

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    Authorship:Lead author   Language:English   Publishing type:Part of collection (book)   Publisher:Springer US  

    DOI: 10.1007/7651_2020_322

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  • Bioinformatic analysis of mechano-sensitive genes and pathways in osteocyte under the mechanical loadings

    Ziyi Wang

    2020.9

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    Authorship:Lead author, Last author   Language:English   Publishing type:Doctoral thesis  

    DOI: 10.18926/60928

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  • Role of intracellular Ca2+–based mechanotransduction of human periodontal ligament fibroblasts Reviewed International journal

    Ei Ei Hsu Hlaing, Yoshihito Ishihara, Ziyi Wang, Naoya Odagaki, Hiroshi Kamioka

    The FASEB Journal   33 ( 9 )   10409 - 10424   2019.7

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

    Abstract
    Human periodontal ligament (hPDL) fibroblasts are thought to receive mechanical stress (MS) produced by orthodontic tooth movement, thereby regulating alveolar bone remodeling. However, the role of intracellular calcium ([Ca2+]i)-based mechanotransduction is not fully understood. We explored the MS-induced [Ca2+]i responses both in isolated hPDL fibroblasts and in intact hPDL tissue and investigated its possible role in alveolar bone remodeling. hPDL fibroblasts were obtained from healthy donors' premolars that had been extracted for orthodontic reasons. The oscillatory [Ca2+]i activity induced by static compressive force was measured by a live-cell Ca2+ imaging system and evaluated by several feature extraction method. The spatial pattern of cell-cell communication was investigated by Moran's I, an index of spatial autocorrelation and the gap junction (GJ) inhibitor. The Ca2+-transporting ionophore A23187 was used to further investigate the role of [Ca2+]i up-regulation in hPDL cell behavior. hPDL fibroblasts displayed autonomous [Ca2+]i responses. Compressive MS activated this autonomous responsive behavior with an increased percentage of responsive cells both in vitro and ex vivo. The integration, variance, maximum amplitude, waveform length, and index J in the [Ca2+]i responses were also significantly increased, whereas the mean power frequency was attenuated in response to MS. The increased Moran's I after MS indicated that MS might affect the pattern of cell-cell communication via GJs. Similar to the findings of MS-mediated regulation, the A23187-mediated [Ca2+]i uptake resulted in the up-regulation of receptor activator of NF-κB ligand (Rankl) and Sost along with increased sclerostin immunoreactivity, suggesting that [Ca2+]i signaling networks may be involved in bone remodeling. In addition, A23187-treated hPDL fibroblasts also showed the suppression of osteogenic differentiation and mineralization. Our findings suggest that augmented MS-mediated [Ca2+]i oscillations in hPDL fibroblasts enhance the production and release of bone regulatory signals via Rankl/Osteoprotegerin and the canonical Wnt/β-catenin pathway as an early process in tooth movement-initiated alveolar bone remodeling.

    DOI: 10.1096/fj.201900484r

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    Other Link: https://onlinelibrary.wiley.com/doi/full-xml/10.1096/fj.201900484R

  • CBCT Analysis of Mesiodistal Angulation of Maxillary Molars for Female Patient with Skeletal Class II Malocclusion Reviewed

    Jun Li, Ziyi Wang, Xiaodong Zhang

    Journal of Oral Science Research   34 ( 8 )   896 - 901   2018.8

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    DOI: 10.13701/j.cnki.kqyxyj.2018.08.023

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  • Role of Osteocyte-PDL Crosstalk in Tooth Movement via SOST/Sclerostin Reviewed

    Odagaki, N., Ishihara, Y., Wang, Z., Ei Hsu Hlaing, E., Nakamura, M., Hoshijima, M., Hayano, S., Kawanabe, N., Kamioka, H.

    Journal of Dental Research   97 ( 12 )   1374 - 1382   2018

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

    DOI: 10.1177/0022034518771331

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  • Efficacy of Glucosamine Hydrochloride Tablets combined with Sodium Hyaluronate in the treatment of Temporomandibular Joint Osteoarthritis Reviewed

    Jianlin Liu, Yansong Wang, Ziyi Wang, Yao Weng

    Progress in Modern Biomedicine   17 ( 2 )   331 - 333   2017.2

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

    DOI: 10.13241/j.cnki.pmb.2017.02.033

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  • Effect of Sodium Hyaluronate Injection and Arthrocentesis for Patients with Temporomandibular Joint Osteoarthritis Reviewed

    WANG Yan-song, LIU Jian-lin, WANG Zi-yi, ZHANG Xiao-dong, CHEN Xi

    Progress in Modern Biomedicine   17 ( 7 )   1304 - 1307   2017.1

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

    DOI: 10.13241/j.cnki.pmb.2017.07.026

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  • Optimization for landmarks-based three-dimensional cephalometric superimposition and a method for superimposition of three-dimensional image of maxilla Reviewed

    Yao Weng, Ziyi Wang, Xiaodong Zhang

    Chinese Journal of Medical Imaging Technology   33 ( 1 )   124 - 131   2017.1

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

    DOI: 10.13929/j.1003-3289.201606089

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  • Relationship between Changes in Thickness of Alveolar Bone and Movement of Maxillary Central Incisor

    Ziyi Wang

    2016.2

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    Authorship:Lead author, Last author   Language:Chinese   Publishing type:Master’s thesis  

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MISC

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Presentations

  • Filamin A mediated epithelial-mesenchymal transition during embryonic palate development

    Ziyi Wang

    The 46th Annual Meeting of Japanese Cleft Palate Association  2022.5.26  Japanese Cleft Palate Association

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    Event date: 2022.5.26 - 2022.5.27

    Language:English   Presentation type:Oral presentation (general)  

    Venue:Kagoshima Kenmin Koryu Center, Yamashitacho, Kagoshima-shi, Kagoshima-ken  

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  • Bioinformatics analysis shows candidate genes for osteocytes differentially response to different types of mechanical stimuli

    Ziyi Wang

    The 77th Annual Meeting of the Japanese Orthodontic Society  2018.10.31  Japanese Orthodontic Society

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    Event date: 2018.10.30 - 2018.11.1

    Language:English   Presentation type:Oral presentation (general)  

    Venue:PACIFICO YOKOHAMA  

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  • Investigate the mechanotransduction of osteocytes: start with bioinformatics

    Ziyi Wang

    14th Advanced Dental School  2018.8.23  International Network of Advanced Dental Education & Research

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    Event date: 2018.8.23 - 2018.8.24

    Language:English   Presentation type:Oral presentation (general)  

    Venue:M&D Tower, Tokyo Medical and Dental University  

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  • Screening of key candidate genes and pathways for osteocytes involved in the differential response to different type of mechanical stimulation using a bioinformatics analysis

    Ziyi Wang

    2018 Tokushima Bioscience Retreat  2018.9.20  Tokushima University

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    Event date: 2018.9.20 - 2018.9.22

    Language:English   Presentation type:Oral presentation (general)  

    Venue:Resort Hotel Olivean Shodoshima  

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  • Screening of key candidate genes and pathways for osteocytes involved in the differential response to different types of mechanical stimulation using a bioinformatics analysis

    Ziyi Wang

    15th Bone Biology Forum  2018.8.17  Bone Biology Forum

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    Event date: 2018.8.17 - 2018.8.18

    Language:English   Presentation type:Oral presentation (general)  

    Venue:Cross Wave Makuhari  

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  • Expression change of circadian clock genes in murine osteocytes by mechanical stimuli: implications for spatial distribution of sclerostin

    Ziyi Wang

    The 38th Annual Meeting of Japanese Society for Bone Morphometry  2018.6.22  Japanese Society For Bone Morphometry

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    Event date: 2018.6.21 - 2018.6.23

    Language:English   Presentation type:Oral presentation (general)  

    Venue:Osaka International House Foundation(i-house)  

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    Other Link: https://www.jsbm.biz/

  • Detection of the bone structure change and periodic osteocytes' expression of sclerostin during orthodontic tooth movement

    Ziyi Wang

    The 59th Annual Meeting of Japanese Association for Oral Biology  2017.9.17  Japanese Association for Oral Biology

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    Event date: 2017.9.16 - 2017.9.18

    Language:English   Presentation type:Oral presentation (general)  

    Venue:Matsumoto Dental University Campus  

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    Other Link: https://www.jaob.jp/publication/meet_abstract_59.html

  • Filamin A mediates embryonic palatal fusion by linking mechanotransduction with β-Catenin/Smad2

    Ziyi Wang

    7th Research Meeting for International Students  2024.3.7  Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University

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    Language:English   Presentation type:Oral presentation (general)  

    Venue:Basic medical lecture building 1st floor multipurpose room  

    Okayama University has been actively engaged in exchanges with foreign universities, including the Okayama University-Northeastern China Graduate Student Exchange (O-NECUS Program) and the JICA Six-University Myanmar Medical Education Enhancement Project. In the Shikata area, more than 80 international students (regular students, special auditing students, special research students, visiting foreign researchers, etc.) from China, Myanmar, Indonesia, and other countries are enrolled, and the number continues to increase. In the laboratory, graduate students and faculty members are actively conducting research in a global environment.

    In order to promote the “Advanced Human Resource Development Program to Promote Sustainable Healthcare Models in ASEAN Core City Regions ” and ” A special PhD course for organ regeneration, tissue reconstruction and integrative biology to collaborate with ASEAN leading medical universities,” as well as to promote exchange and information sharing among international students, faculty members, and staff, the 7th International Student Research Presentation was held.

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    Other Link: https://www.mdps.okayama-u.ac.jp/en/news_events/7th-international-student-research-presentation-notice/

  • The role of circadian rhythm and cell-to-cell communications in osteocytes mechanotransduction Invited International conference

    Ziyi Wang

    Bone-Bio-Engineering Kick-off Symposium  2020.9.30  STINT-JSPS Bilateral Joint Research Project Okayama University (Japan), Linköping University (Sweden)

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    Language:English   Presentation type:Symposium, workshop panel (nominated)  

    Venue:Online  

    This Bilateral Joint Research Project, supported by STINT and JSPS, aims to promote international and interdisciplinary collaborations between Linkoping and Okayama Universities in Bone Biology and Material Science and Engineering.

    This kick-off meeting will gather multidisciplinary speakers on topics ranging from understanding the theoretical basis of bone development and metabolism to developing novel materials for application in bone tissue engineering.

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  • Changes of the spatial distribution of sclerostin may subject to the control of circadian rhythm in osteocytes during orthodontic tooth movement International conference

    Ziyi Wang

    The 4th International Symposium of Medical and Dental Education in Okayama  2019.12.14  Okayama University

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    Language:English   Presentation type:Oral presentation (general)  

    Venue:Lecture Room 1, Dental School of Okayama University  

    The "Okayama Dental Association," composed of faculty and students from the Okayama University Faculty of Dentistry, held the "4th Okayama Medical Education International Symposium" in the first lecture hall of our Faculty of Dentistry on December 14th. This symposium was held with the aim of building international collaborations among dental universities in the fields of education and research. Deans or hospital directors from two universities in Indonesia, two in Vietnam, and one each from the Netherlands, the United States, and China were invited to share information about their unique education and research systems. More than 200 dentistry faculty members and students participated, and there were lectures (two sessions) by invited speakers, as well as presentations and poster sessions by ODAPUS students, O-NECUS students, graduate students, and young researchers from abroad. The symposium began with a lecture by Associate Professor Muhammad Ruslin from Hasanuddin University, and included research presentations and introductions of universities by ten researchers and seven undergraduate and graduate students, including ODAPUS and O-NECUS exchange students. There was a Q&A session for the 24 posters presented on the floor, and lively discussions were held in all sessions. Eman A. Taha (in the field of dental pharmacology), Ha Thi Thu Nguyen (in the field of implant regenerative prosthodontics), Islam Md Monirui (in the field of preventive dentistry), and Assistant Professor Hokuto Kawai (in the field of oral pathology) were awarded the Excellent Poster Award for their outstanding poster presentations. The symposium was actively participated in not only by faculty members but also by undergraduate and graduate students involved in various exchange programs. It was a good opportunity for the next generation of dental students and young researchers, who will lead the future development of dentistry and dental care, to gain the knowledge and experience necessary for international academic exchange.

    ODAPUS: Okayama University Dental School Short-term Study Abroad Program for Undergraduate Students
    O-NECUS: Okayama University-North East China Universities platform, 'Graduate' Student Exchange Program

    The symposium was conducted with support from Astellas Pharma Educational Support and Alpha Bio Co., Ltd.

    Presenters and Contents:

    Associate Professor Muhammad Ruslin (Hasanuddin University): Current state and future of dental care in Indonesia
    Associate Professor Tong Minh Son (Hanoi Medical University): Oral health status of the elderly in Vietnam
    Professor Vu Quang Hung (Haiphong Medical University): Introduction to Haiphong Medical University
    Associate Professor Tianna Wahyu Utami (Gadjah Mada University): Efficacy of oil from Scorodocarpus borneensis leaves
    Professor Hongchen Sun (China Medical University): Role of Acvr1 in dentin formation
    Professor Albert Feilzer (Academic Center for Dentistry Amsterdam): Side effects of dental materials
    Professor Igor Spigelman (University of California, Los Angeles (UCLA)): About novel non-psychoactive cannabinoids for chronic pain treatment
    Yuji Komiyama (5th year, Faculty of Dentistry, our university), Kazuho Natsume (3rd year, same), Dr. Nur Mohammad Hassan (Charles Sturt University): Lectures related to the ODAPUS program
    Yuhan He (China Medical University, O-NECUS student in 2019), Qianqian Lu (Jilin University, O-NECUS student in 2019): Introduction to their home universities
    Akhter Mst Nahid (Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, our university, in the field of biomaterials), May Wathone Oo (in the field of oral pathology), Ei Ei Hsu Hlaing (in the field of orthodontics): Research presentations
    Associate Professor Heni Susilowati (Gadjah Mada University), Dr. Pham Thanh Hai (Haiphong Medical University): Lectures on research content
    [Contact for inquiries]
    Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
    Mika Ikegame, Hirohiko Okamura
    TEL: 086-235-6632
    E-mail: ikegame@md.okayama-u.ac.jp; hiro-okamura@okayama-u.ac.jp

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Works

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Awards

  • Best oral presentation

    2018.10   The 77th Annual Meeting of the Japanese Orthodontic Society   Bioinformatics analysis shows candidate genes for osteocytes differentially response to different types of mechanical stimuli

    Ziyi Wang

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    Award type:Award from Japanese society, conference, symposium, etc.  Country:Japan

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  • Best poster presentation

    2018.10   The 77th Annual Meeting of the Japanese Orthodontic Society   Static force induces change of circadian clock genes in murine osteocytes might change sclerostin distribution

    Ziyi Wang

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    Award type:Award from Japanese society, conference, symposium, etc.  Country:Japan

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  • Excellent oral presentation of the14th Advanced Dental School

    2018.8   International Network of Advanced Dental Education & Research   Investigate the mechanotransduction of osteocytes: start with bioinformatics

    Ziyi Wang

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    Award type:Award from Japanese society, conference, symposium, etc.  Country:Japan

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  • Excellent poster presentation

    2018.7   The 36th Annual Meeting of the Japanese Society for Bone and Mineral Research   Mechanical signals influence circadian clock genes in murine osteocytes: implications for spatial distribution of sclerostin

    Ziyi Wang

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    Award type:Award from Japanese society, conference, symposium, etc.  Country:Japan

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  • The Best Presentation of the 7th Research Meeting for International Students in Okayama University

    2024.3   Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University   Filamin A mediates embryonic palatal fusion by linking mechanotransduction with β-Catenin/Smad2

    Ziyi Wang

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    Award type:Award from Japanese society, conference, symposium, etc.  Country:Japan

    Okayama University has been actively engaged in exchanges with foreign universities, including the Okayama University-Northeastern China Graduate Student Exchange (O-NECUS Program) and the JICA Six-University Myanmar Medical Education Enhancement Project. In the Shikata area, more than 80 international students (regular students, special auditing students, special research students, visiting foreign researchers, etc.) from China, Myanmar, Indonesia, and other countries are enrolled, and the number continues to increase. In the laboratory, graduate students and faculty members are actively conducting research in a global environment.

    In order to promote the “Advanced Human Resource Development Program to Promote Sustainable Healthcare Models in ASEAN Core City Regions ” and ” A special PhD course for organ regeneration, tissue reconstruction and integrative biology to collaborate with ASEAN leading medical universities,” as well as to promote exchange and information sharing among international students, faculty members, and staff, the 7th International Student Research Presentation was held.

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Research Projects

  • Elucidating the Mechanisms of Palatal Development by Combining Molecular Biology and Information Biology

    Grant number:22KF0265  2022.03 - 2024.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for JSPS Fellows

    Toshitaka Oohashi, Ziyi Wang

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    Grant amount:\2300000 ( Direct expense: \2300000 )

    王博士は,公開されている大規模なゲノムワイド関連解析データを活用した口蓋裂の発生に関わる一塩基多型 (SNP)解析,および,マウス口蓋組織の器官培養実験を行い,メカニカルストレスとWntシグナル経路が口蓋の発生において重要な役割を担っている事実を掴んだ.しかし,未だその詳細なメカニズムは不明である.一方,当研究室では,1細胞遺伝子解析や空間的遺伝子解析など,最近の技術を取り入れながら,骨の発生や再生過程に関する研究を展開している. そこで,本申請研究では彼のこれまでの研究成果を基盤に,我々の有する最新の分子生物学的解析手法を加え,口唇・口蓋を含めた顎顔面の発生メカニズムを明らかにする.
    今年度は,すでに所有している空間的遺伝子解析 (Visium Spatial Gene Expression, 10x Genomics)結果を用いて,口蓋に焦点を置き解析を行った.しかし,発生期の口蓋組織は小さく,Visiumの解像度では解析が難しいことがわかった.そこで,NanoString社の空間的遺伝子解析のアプリケーションを用いるため,酵素処理や抗体染色の条件検討を行い,染色条件を絞り込むことができた.また,マウス胎生期の口蓋発生に関するsingle cell RNA-seqの公開データをダウンロードし,再解析を行った.その結果,口蓋の発生に関わる遺伝子の抽出に成功した.そこで,胎生期の口蓋組織を用いた3次元モデルにて,抽出遺伝子の機能解析を行った.その結果,抽出された遺伝子群の中に,口蓋の発生に深く関わっている遺伝子があることが明らかとなった.

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  • Investigating the mechanism to regulate osteocytes by circadian rhythm that effected by the crosstalk with periodontal ligament cells

    Grant number:19J11906  2019.04 - 2021.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for JSPS Fellows

    Ziyi Wang

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\2300000 ( Direct expense: \2300000 )

    骨細胞の細胞間コミュニケーションが骨代謝に与える研究を始めました。そして、細胞間コミュニケーション速度を定量的に測る方法を確立し、著名なSpringer社のプロトコルブックシリーズ(Methods in Molecular Biology)から招待を受けました。また、骨細胞の機械刺激応答の研究を進め、その応答は細胞間コミュニケーション速度に依存していることを突き止めました。さらに、骨細胞が機械的刺激を感知するために重要な候補遺伝子とその経路を、公開遺伝子チップデータを使ったバイオインフォマティクス解析を行い、低酸素症、概日リズム、エネルギー代謝に関わる遺伝子が骨細胞の機械刺激応答に重要な役割を果たすことを明らかにしました。そして、エネルギー代謝の時空間的パターンが、機械的刺激に応答して骨と他の臓器系との間の相互作用を調節する新たな可能性を示唆することができました。よって、期待以上の進展があったことをご報告致します。

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  • Challenge to elucidate the mechanism of cleft palate development from gene expression analysis linked to spatial information

    Grant number:22K19624  2022.06 - 2025.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Research (Exploratory)

    上岡 寛, 早野 暁, 大野 充昭

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    Grant amount:\6500000 ( Direct expense: \5000000 、 Indirect expense:\1500000 )

    本研究目的である、口蓋発生メカニズムの解明のため、口蓋突起癒合部におけるFillamin A (Flna)の発現に注目し、主に次の4項目の研究を実施した。一つ目は、マウス胎児口蓋の培養法を用いた器官培養実験であり、口蓋突起部上皮消失の重要な因子であるTGF-βとFlnaとの関係を検討した。具体的にはTGF-β阻害薬およびTGF-βの下流で活性化するRhoA阻害薬、さらに、siRNAを用いたFlnaのノックダウンを行い、器官培養中の口蓋での反応を観察した。この結果、TGF-β阻害薬およびRhoA阻害薬を添加した口蓋では、Flnaタンパクの産生が著しく低下していた。これらのことからFlnaは既報のTGF-βやRhoAシグナルの下流で働いていることが示唆された。二つ目は、上記の器官培養法で得られた上記の結果をより詳細に調べるため、ヒト表皮角化細胞であるHaCat細胞を用いてTGF-β経路下流で発現するFlnaと上皮間葉転換についてin vitro実験を行なった。この結果の解釈に関しては追加で実験を行う必要があると考えられる。三つ目は、遺伝子改変マウスの作成である。上皮細胞特異的にFlnaをノックダウンさせるため、KRT14-CreマウスとFlna floxマウスをどちらもJackson Laboratoryから購入した。凍結胚からそれぞれの遺伝子改変マウスを作出し、現在交配を続けている。現段階で交配に問題は認められず、約3か月程度で目的のマウスが得られる予定である。また、四つ目としてNanostring社のGeoMXを用いた空間的トランスクリプトーム解析を行うための準備実験を行なった。本研究の予備実験として既にVisiumを用いたトランスクリプトーム解析を行なっているが、Flnaに特化した更なる解析を予定している。

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  • Filamin A mediated epithelial-mesenchymal transition during embryonic palate development

    Grant number:22K10245  2022.04 - 2025.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Storu Hayano, Takashi Izawa, Takeshi Takarada

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    Authorship:Collaborating Investigator(s) (not designated on Grant-in-Aid) 

    Grant amount:\4160000 ( Direct expense: \3200000 、 Indirect expense:\960000 )

    本研究の目的である、口蓋突起癒合部におけるFillamin A (Flna)の発現が口蓋の発生に与える影響を調べるため、本年度は主に以下の3項目の研究を実施した。
    ①器官培養実験:我々がこれまでに確立してきた、マウス胎児口蓋の器官培養法を用いて、口蓋突起部上皮消失の重要な因子であるTGF-βとFlnaとの関係を検討した。具体的にはTGF-β阻害薬およびTGF-βの下流で活性化するRhoA阻害薬、さらに、siRNAを用いたFlnaのノックダウンを行い、器官培養中の口蓋でどのような反応が生じるかを観察した。この結果、TGF-β阻害薬およびRhoA阻害薬を添加した培養液を用いたマウス胎児口蓋では、Flnaタンパクの産生が著しく低下していた。これらのことからFlnaは既報のTGF-βやRhoAシグナルの下流で働いていることが示唆された。
    ②In vitro実験:器官培養法で得られた上記の結果をより詳細に調べるため、ヒト表皮角化細胞であるHaCat細胞を用いてTGF-β経路下流で発現するFlnaと上皮間葉転換について検討した。この結果の解釈に関しては追加で実験を行う必要があると考えられる。
    ③遺伝子改変マウスの作成:上皮細胞特異的にFlnaをノックダウンさせるため、KRT14-CreマウスとFlna floxマウスをどちらもJackson Laboratoryから購入した。凍結胚からそれぞれの遺伝子改変マウスを作出し、現在交配を続けている。現段階で交配に問題は認められず、約3か月程度で目的のマウスが得られる予定である。
    また、上記項目以外に、Nanostring社のGeoMXを用いた空間的トランスクリプトーム解析を行うための準備実験を行なった。具体的には、胎生14日マウス胎児口蓋のパラフィン切片を作成し、パラフィン切片でも検出できるFlna抗体の選定を行なった。

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  • Challenge for analyzing the dysfunctional mechanism of oral barrier repair via dioxin receptor due to smoking

    Grant number:21K19602  2021.07 - 2024.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Research (Exploratory)

    井澤 俊, 加治屋 幹人, 早野 暁

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    Grant amount:\6500000 ( Direct expense: \5000000 、 Indirect expense:\1500000 )

    近年、大気中のPM2.5やタバコの煙に含まれるダイオキシン類による健康への影響に社会的関心が高まり毒性リスクの評価や環境基準値の設定が求められている。歯を支持する役割を担う歯周組織は、食事に伴う咬合力の負担に耐えるために、他の組織に比べて代謝や修復が盛んに行われている。そのため、タバコの煙に毎日暴露されている歯周組織への悪影響は顕著とならざるを得ない。このような口腔の解剖学的特徴により、タバコの煙は様々な面で口腔に悪影響を及ぼす。ダイオキシン受容体として知られる転写因子AhRは、様々な組織に発現がみられ、最近になって一部の免疫細胞にも高発現していることが明らかになってきている。内分泌撹乱物質を含む喫煙が歯周炎や口唇口蓋裂のリスクファクターであることは疫学的にはよく知られた事実であるが、そのメカニズムは十分に明らかにされていない。核内受容体として知られるAhRに対する各種AhRリガンドが喫煙によって生じるタバコの煙中に多く含まれる。その中でも強力なAhRリガンドの一つがベンツピレン(benzo[a]pyrene; B[a]P)である。そこで、タバコの粒子相成分の一つであるB[a]P等が結合するAhRに着目した。本研究ではマクロファージにおけるB[a]P/AhRシグナル伝達経路を詳細に解析し、喫煙などによって生じる化学物質などの外的因子が口蓋の創傷治癒に及ぼす影響について検討することとした。野生型マウスにB[a]Pを経口投与後、口蓋粘膜創傷治癒解析を行った結果、B[a]P投与群において創傷治癒が遅延していることを明らかにし、さらに細胞系譜解析とパラビオース解析を組み合わせることでB[a]P経口投与マウスでは組織修復マクロファージの集積が破綻していることを予備実験により見出している。

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  • Elucidation of mechanosensor function acquisition process of osteocytes using 3D-volumetric image data

    Grant number:19H03859  2019.04 - 2023.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    Kamioka Hiroshi

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    Grant amount:\17160000 ( Direct expense: \13200000 、 Indirect expense:\3960000 )

    We considered bone as a continuum of matrix structure and cell structure, and thought that the construction of the two would allow osteocytes to mature as mechanosensors. In this study, we found that it is important for osteocyte processes to form a certain structure with the surrounding osteocyte processes in order for osteocytes to function as mechanosensors, and the key is the formation of a tethering element between them. Furthermore, in the future, in order to examine the effects of osteocyte canaliculi formation on mechanical stress response for bone disease, automatic extraction of cell processes and bone tubules will be essential. It became clear that machine learning can be applied to the analysis of FIB-SEM data.

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  • Analysis dynamics of HMGB1 as a biosensor molecule and its multiple functions

    Grant number:19H03408  2019.04 - 2022.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    Nishibori Masahiro

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    Grant amount:\17550000 ( Direct expense: \13500000 、 Indirect expense:\4050000 )

    Dynamics of a representative DAMP, HMGB1, was examined using vascular endothelial cells (EA.hy926). Histamine concentration-dependently induced the translocation and release of HMGB1 from vascular endothelial cells by the stimulation of H1-receptor subtype, which was mimicked by selective H1- receptor agonist, 2-pyridyl-ethylamine. Mast cell stimulator, compound 48/80, induced an anaphylactic hypotensive shock in rats, associated with the elevation of plasma HMGB1. The treatment with anti-HMGB1 mAb (#10-22) significantly facilitated the recovery from hypotensive shock.
    LPS and TNF-α induced a similar HMGB1 release from vascular endothelial cells, associated with the secretion of IL-6 and IL-8. All these responses were inhibited by anti-HMGB1 mAb (#10-22). Taken together, it was concluded that HMGB1 in vascular endothelial cells may respond to many stimulants.

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  • Epigenetic analysis of regulating bone and mineral metabolism under rare disease in orthognathic lesion

    Grant number:18KK0464  2019 - 2023

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Fund for the Promotion of Joint International Research (Fostering Joint International Research (A))

    井澤 俊

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    Grant amount:\15600000 ( Direct expense: \12000000 、 Indirect expense:\3600000 )

    喫煙が骨粗鬆症や骨折のリスクファクターであることは疫学的によく知られた事実であるが、そのメカニズムは十分に明らかにされていない。タバコの煙の中で最も強力な化学物質の一つがbenzo[a]pyrene(B[a]P)であり、アリルハイドカーボンレセプター(aryl hydrocarbon receptor:AhR)を活性化することが知られている。そこで、骨折などの病的状況下でのB[a]PとAhRシグナル伝達機構の影響解明や新たな骨代謝疾患の診断や治療法の開発を目的とする。マウスに骨折やB[a]Pを経口投与後、大腿骨部、脛骨、下顎頭部を摘出し、脱灰後に各種組織学的解析や免疫学的解析を実施する。また、マウス大腿骨から骨髄細胞を採取し、AhRリガンドのB[a]Pや内因性リガンドの6-formylindolo[3,2-b]carbazole(FICZ)刺激による破骨細胞形成能を培養系において比較する。アポトーシスの指標の一つCaspase 3の分断化について下顎頭部での発現解析を行ったところ、WTマウスにおいてB[a]P経口投与群では著明な発現上昇を示した一方で、AhR-/-マウスではB[a]P経口投与による変化はみられなかった。また、今年度はマウスの骨折モデルを確立することができた。さらにin vitroでの破骨細胞形成能において、B[a]Pの濃度依存的に破骨細胞形成能の増加、一方で内因性のAhR リガンドの一つFICZでは濃度依存的に破骨細胞形成能の低下を認めた。AhRリガンドであるB[a]P及びFICZ投与が下顎頭において各々異なる作用を示し、AhRリガンド刺激によるアポトーシスシグナルを介したAhR活性化経路が破骨細胞分化や骨折治癒過程において重要な役割を果たしていることが示唆された。

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  • Epigenetic analysis of new bone remodeling mechanism in the dentofacial region.

    Grant number:18H03011  2018.04 - 2022.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    Izawa Takashi

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    Grant amount:\17290000 ( Direct expense: \13300000 、 Indirect expense:\3990000 )

    It remains unclear whether the AhR signaling affects the TMJ. The aim of this study was to investigate possible mechanisms of bone loss in the TMJ due to the epigenetic alteration such as smoking. In particular, whether benzo[a]pyrene (B[a]P) induces expression of Cyp1a1 in the mandible. Possible functions of an endogenous ligand FICZ were investigated in a TMJ-OA mouse model. B[a]P was administered orally to mice and bone metabolism was examined. TMJ-OA was induced in WT mice with forceful opening of the mouth, and therapeutic functions of FICZ were detected. Exposure to B[a]P accelerated bone loss in the mandible. This bone loss manifested with osteoclastic bone resorption. In a TMJ-OA model, FICZ exhibited a dose-dependent rescue of subchondral bone loss by repressing osteoclast activity. Pretreatment with FICZ reduced RANKL-mediated osteoclastogenesis. B[a]P regulates subchondral bone metabolism via the Cyp1a1. FICZ can prevent TMJ-OA by regulating osteoclast differentiation.

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  • Regulation of tooth movement-initiated mechanotransduction via osteocytic bone remodeling

    Grant number:17H04413  2017.04 - 2021.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    ISHIHARA Yoshihito

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    Grant amount:\16770000 ( Direct expense: \12900000 、 Indirect expense:\3870000 )

    Orthodontic tooth movement (OTM) is achieved by the remodeling of the periodontal ligament (PDL) and alveolar bone in response to balanced mechanical loading. We investigated the regulatory dynamics of the SOST/Scl expression generated by orthodontic tooth movement (OTM) in vivo and in vitro. Our results provide evidence to support that factors secreted by the PDL, including SOST/Sclerostin, control alveolar bone remodeling through osteocytic SOST/Sclerostin in OTM. In addition, our findings suggest that augmented mechanical stress-mediated Ca2+ oscillations in PDL enhance the production and release of bone regulatory signals.

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  • Functional analysis of RPL5 using induced pluripotent stem cells from the patient with Diamond-Blackfan Anemia

    Grant number:17K17323  2017.04 - 2019.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Young Scientists (B)

    Hayano Satoru, SHIMADA Akira, SAITO Megumu, KAMIOKA Hiroshi, KAWANABE Noriaki, Fukui Yuko

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    Grant amount:\4030000 ( Direct expense: \3100000 、 Indirect expense:\930000 )

    In this study, we focused on Diamond-Blackfan anemia (DBA), which is characterized by red blood cell aplasia and craniofacial defects. iPS cells derived from DBA patient was used in this study. Our current study indicates that craniofacial defect is caused by activation of p53-mediated cell death pathway which is induced by interaction between ribosomal proteins and MDM2.

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