Investigation of molecular mechanisms of Sox9 transcriptional factory during enchandral ossification

• Project/Area Number: 17209059
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Functional basic dentistry
• Research Institution: Osaka University
• Principal Investigator: YONEDA Toshiyuki Osaka University, Graduate School of Dentistry, Professor (80142313)
• Co-Investigator(Kenkyū-buntansha): NISHIMURA Rikou Osaka University, Graduate School of Dentistry, Associate Professor (60294112) ; 平賀 徹 大阪大学, 大学院・歯学研究科, 講師 (70322170)
• Project Period (FY): 2005 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥46,800,000 (Direct Cost: ¥36,000,000、Indirect Cost: ¥10,800,000); Fiscal Year 2007: ¥15,340,000 (Direct Cost: ¥11,800,000、Indirect Cost: ¥3,540,000); Fiscal Year 2006: ¥15,340,000 (Direct Cost: ¥11,800,000、Indirect Cost: ¥3,540,000); Fiscal Year 2005: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000)
• Keywords: chondrocyte / transcriptional factory / Sox9

Research Abstract

Tb investigate the molecular mechanism by which Sox9 plays an essential role in chondrocyte differentiation, we established a gene screening system for identifying the members of Sox9 transcriptional factory. Using this system, we could identify a calcium ion channel, TRPV_4, as a member of Sox9 transcriptional factory, and found that TRPV4 upregulated expression and function of Sox9, thereby stimulating chondrocyte differentiation. We further screened cDNA library generated from chondrogenic cell line, ATDC5, and isolated the Znf219 cDNA. Whole mount in situ and RT-PCR analyses indicated that Znf219 is specifically expressed in limb bud of E12.5 embryo mice and chondrocytes. Co-immunoprecipitation experiments indicated that Znf219 physically interacts with Sox9. Moreover, we found that Znf219 co-localized with Sox9 in the nucleus. These results indicated that Znf219 forms transcriptional factory in the nucleus. To understand the functional role of Znf219 m chondrocyte differentiation, we next examined the effect of overexpression of Zof219 on chondrocyte differentiation. We found that overexpression of Znf219 stimulated the chondrogenic activity of Sox9. In contrast, overexpression of a dominant negative Znf219 markedly inhibited chondrocyte differentiation induced by Sox9. Furthermore, knockdown of Znf219 using micro RNA system suppressed chondrocyte differentiation. Collectively, our results demonstrated that Znf219 might play an important role in Sox9-regulated chondrocyte differentiation.

Research Products

• [Journal Article] JNK/c-Jun signaling mediates anti-apoptotic effect of RANKL in osteoclasts (2008)
  • Author(s): Ikeda F, et. al.
  • Journal Title: J Bone Miner Res 41(印刷中)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Phenotypic analysis of Dlx5 overexpression in post-natal bone (2008)
  • Author(s): Zhang, J, Zhu, J, Valverde, P, Li, L, Pageau, S, Tu, Q, Nishimura, R, Yoneda, T, Yang, P, Zheng, W, Ma, W, Chen, J
  • Journal Title: J Dent Res 87 Pages: 45-50
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Functional gene screening system identified TRPV4 as a regulator of chondrogenic differentiation (2007)
  • Author(s): Muramatsu, et. al.
  • Journal Title: J Biol Chem 282 Pages: 32158-67
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Ihh/Gli2 signaling promotes osteoblast differentiation by regulating Runx2 expression and function. (2007)
  • Author(s): Shimoyama, et. al.
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  • Description: 「研究成果報告書概要(和文)」より
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• [Journal Article] Differential expression of matrix metalloproteinases in brain- and bone-seeking clones of metastatic MDA-MB-231 breast cancer cells (2007)
  • Author(s): Stark, AM, Palmieri, D, Meter, PS, Walker, RT, Mentlein, R, Yoneda, T, Mehdorn, HM, Steeg, PS, Held-Feindt, J
  • Journal Title: J Neurooncol 81 Pages: 39-48
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Acidic microenvironment created by osteoclasts causes bone pain associated with tumor colonization (2007)
  • Author(s): Nagae, M, Hiraga, T, Yoneda, T
  • Journal Title: J Bone Miner Metab 25 Pages: 99-104
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Her-2 overexpression increases the metastatic outgrowth of breast cancer cells in the brain (2007)
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• [Journal Article] NAD(P)H oxidases regulate HIF-2a protein expression (2007)
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• [Journal Article] Hypoxia, and HIF-1 expression enhance osteolytic bone metastases of breast cancer (2007)
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• [Journal Article] lhh/Gli2 signaling promotes osteoblast differentiation by regulating Runx2 expression and function (2007)
  • Author(s): Shimoyama, A, Wada, M, Ikeda, F, Hata, K, Matsubara, T, Nifuji, A, Noda, M, Amano, K, Yamaguchi, A, Nishimura, R, Yoneda, T
  • Journal Title: Mol Biol Cell 18 Pages: 2411-2418
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Phosphate deprivation inhibits osteoclast differentiation and function (2007)
  • Author(s): Hayashibara, T, Hiraga, T, Ooshima, T, Yoneda, T
  • Journal Title: J Bone Miner Res 22 Pages: 1743-1751
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Functional gene screening system identified TRPV4 as a regulator of chondrogenic differentiation (2007)
  • Author(s): Muramatsu, S, Wakabayashi, M, Ohno, T, Ooishi, R, Sugahara, T, Shiojiri, S, Suzuki, Y, Sugano, S, Nishimura, R, Yoneda, T, Matsuda, A
  • Journal Title: J Biol Chem 282 Pages: 32158-32167
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Functional gene screening system identified TRPV4 as a regulator of chondrogenic differentiation (2007)
  • Author(s): Muramatsu S, et. al.
  • Journal Title: J Biol Chem 282 Pages: 32158-67
  • Peer Reviewed
• [Journal Article] Ihh/Gli2 signaling promotes osteoblast differentiation by regulating Runx2 expression and function. (2007)
  • Author(s): Shimoyama A, et. al.
  • Journal Title: Mol Biol Cell 18 Pages: 2411-2418
  • Peer Reviewed
• [Journal Article] RANK ligand signaling modulates the matrix metalloproteinase-9 gene expression during osteoclast differentiation. (2007)
  • Author(s): Sundaram K et al.
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• [Journal Article] Sustained phosphorylation of mutated FGFR3 is a crucial feature of genetic Dwarfism and induced apoptosis of ATDC5 chondrogenic cell line via PLC_Y-acvated STAT1. (2007)
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  • Journal Title: Bone (印刷中)
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• [Journal Article] Activation of NFAT signal in vivo leads to osteopenia associated with increased osteoclastogenesis and bone resorbing activity (2006)
  • Author(s): Ikeda, F, Nishimura, R, Matsubara, T, Hata, K, Reddy, SV, Yoneda, T
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  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Critical role of cortactin in actin ring formation and osteoclastic bone resorption (2006)
  • Author(s): Matsubara, T, Myoui, A, Ikeda, F, Hata, K, Yoshikawa, H, Nishimura, R, Yoneda, T
  • Journal Title: J Bone Miner Metab 24 Pages: 368-372
  • NAID: 10018193329
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Osteoclasts play a part in pain due to the inflammation adjacent to bone (2006)
  • Author(s): Nagae, M, Hiraga, T, Wakabayashi, H, Wang, L, lwata, K, Yoneda, T
  • Journal Title: Bone 39 Pages: 1107-1115
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• [Journal Article] Ac-Fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model (2006)
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• [Journal Article] Co-localization of cortactin and phosphotyrosine identifies active invadopodia in human breast cancer cells (2006)
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• [Journal Article] In vivo MRI of cancer cell fate at the single cell level in a mouse model of breast cancer metastasis to the brain (2006)
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  • Journal Title: Magnetic Resonance Med 56 Pages: 1001-1010
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• [Journal Article] Activation of NFAT signal in vivo leads to osteopenia associated with increased osteoclastogenesis and bone resorbing activity. (2006)
  • Author(s): Ikeda F et al.
  • Journal Title: Journal of Immunology 177 Pages: 2384-2390
• [Journal Article] CCAAT/enhancer-binding protein homologous protein (CHOP) negatively regulates bone morphogenetic protein (BMP)-induced osteoblast differentiation of mesenchymal cells. (2006)
  • Author(s): Shirakawa K et al.
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• [Journal Article] Critical role of Cortactin in actin ring formation and osteoclastic bone resorption. (2006)
  • Author(s): Matsubara T et al.
  • Journal Title: Journal of Bone Mineral and Metabolism 24 Pages: 368-372
• [Journal Article] Stimulation of Cyclooxygenase-2 Expression by Bone-Derived Transforming Growth Factor-β Enhances Bone Metastases in Breast Cancer. (2006)
  • Author(s): Hiraga T
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• [Journal Article] CCAAT/enhancer binding protein β isoform, liver-enriched inhibitory protein, regulates commitment of osteoblasts and adipocytes (2005)
  • Author(s): Hata, K, Nishimura, R, Ueda, M, Ikeda, F, Matsubara, T, lchide, F, Hisada, K, Nokubi, T, Yamaguchi, A, Yoneda, T
  • Journal Title: Mol Cell Biol 25 Pages: 1971-1979
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• [Journal Article] Crosstalk between cancer cells and bone microenvironment in bone metastasis (2005)
  • Author(s): Yoneda, T, Hiraga, T
  • Journal Title: Biochem Biophys Res Commun 328 Pages: 679-687
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• [Journal Article] Preferential inhibition of bone metastases by 5'-deoxy-5-fluorouridine and capecitabine in the 4T1/luc mouse breast cancer model (2005)
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  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Crosstalk between cancer cells and bone microenvironment in bone metastasis. (2005)
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• [Journal Article] Preferential inhibition of bone metastases by 5'-deoxy-5-fluorouridine and capecitabine in the 4T1/luc mouse breast cancer model. (2005)
  • Author(s): Hiraga T
  • Journal Title: Oncol Rep 14・3 Pages: 695-699
• [Presentation] Control of chondrocyte differentiation by transcription factors (2008)
  • Author(s): Yoneda, T
  • Organizer: 7th Annual Meeting of the Japanese Society for Regenerative Medicine
  • Place of Presentation: Nagoya, Aichi
  • Year and Date: 2008-03-14
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Cancer and bone microenvironment (2007)
  • Author(s): Yoneda, T
  • Organizer: Osaka University-UCSF Joint Symposium, San Francisco, CA
  • Place of Presentation: USA
  • Year and Date: 2007-11-28
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Osteoblastic bone metastases (2007)
  • Author(s): Yoneda, T
  • Organizer: 1st Setouchi Forum
  • Place of Presentation: Okayama
  • Year and Date: 2007-08-19
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] β-Trcp1ユビキチン化システムによるIhh/Gli2誘導性骨芽細胞分化の制御 (2007)
  • Author(s): 和田 誠大, ら
  • Organizer: 日本骨代謝学会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2007-07-19
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Origination of Frontier Biodentistry. Understanding of the molecular mechanism of oral diseases and its clinical application (2007)
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  • Organizer: 61st Annual Meeting of the Japanese Stomatological Society
  • Place of Presentation: Kobe
  • Year and Date: 2007-04-19
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Biology of cancer-induced bone diseases (2006)
  • Author(s): Yoneda, T
  • Organizer: Satellite Symposium, Japanese Association of Cancer Research
  • Place of Presentation: Yokohama, Kanagawa, Japan
  • Year and Date: 2006-09-29
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Role of phosphate in endochondral ossification (2006)
  • Author(s): Yoneda, T
  • Organizer: 20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOBMB Congress
  • Place of Presentation: Kyoto, Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] 分子生物硬組織研究のイノベーション (2008)
  • Author(s): 西村 理行
  • Total Pages: 22
  • Publisher: 大阪大学出版会
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 分子生物硬組織研究のイノベーション (2008)
  • Author(s): 西村 理行
  • Publisher: 大阪大学出版会(印刷中)