Role of Irx3 in chondrogenic differentiation and chondrocyte maturation of mouse mesenchymal cells

• Project/Area Number: 26462805
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Morphological basic dentistry
• Research Institution: Mukogawa Women's University
• Principal Investigator: Tamamura Yoshihiro 武庫川女子大学, 健康・スポーツ科学部, 博士研究員 (70431963)
• Co-Investigator(Renkei-kenkyūsha): WAKITANI Shigeyuki 武庫川女子大学, 健康スポーツ科学部, 教授 (70243243) ; MERA Hisashi 新潟大学, 地域医療教育センター魚沼基幹病院, 講師 (70650381)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: Irx3 / 軟骨細胞 / Wntシグナル / p38シグナル / MAPK / 間葉系細胞 / 転写調節因子

Outline of Final Research Achievements

Sox9 is known to be a master regulator of cartilage development. In this study, we attempted to identify genes involved in Sox9-independent regulatory mechanisms of chondrocyte differentiation and focused on Irx3. Irx3 expression gradually increased with chondrocyte terminal differentiation and promoted the chondrogenic differentiation of mesenchymal cells upon Bmp2 treatment. Irx3 partially rescued impaired chondrogenesis via upregulating the expression of epiphycan and lumican by activating the p38 MAPK pathway under reduced Sox9 expression. Moreover, Irx3 stimulates chondrocyte maturation by Wnt signaling. This function of Irx3 might be resulted in part from activation of Wnt signaling augmented by R-spondin1-Lgr6 interaction. These results indicate that Irx3 represents a novel regulatory factor of chondrocyte differentiation and regulates chondrogenesis independent of the transcriptional machinery associated with Sox9-mediated regulation.

Research Products

• [Journal Article] Irx3 and Bmp2 regulate mouse mesenchymal cell chondrogenic differentiation in both a Sox9-dependent and -independent manner (2017)
  • Author(s): Tamamura Y, Katsube K, Mera H, Itokazu M, Wakitani S
  • Journal Title: J. Cell. Physiol. Volume: 印刷中 Issue: 12 Pages: 3317-3336
  • DOI: 10.1002/jcp.25776
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transplantation of Scaffold-free Cartilage-Like Cell Sheets Made from Human Bone Marrow Mesenchymal Stem Cells for Cartilage Repair: Preclinical Study (2016)
  • Author(s): Maki Itokazu, Shigeyuki Wakitani, Hisashi Mera, Yoshihiro Tamamura, Yasushi Sato, Mutsumi Takagi, Hiroaki Nakamura
  • Journal Title: Cartilage Volume: 9 Issue: 4 Pages: 1-12
  • DOI: 10.1177/1947603515627342
  • Peer Reviewed
• [Journal Article] 骨髄間葉系幹細胞からの軟骨様細胞シートの作成および移植（前臨床試験） (2015)
  • Author(s): 糸数万紀、目良恒、玉村禎宏、高木睦、脇谷滋之
  • Journal Title: 関節外科 Volume: 34 Pages: 108-117
• [Presentation] 転写調節因子Irx3はWntシグナルにより軟骨細胞分化を調節し、そのシグナル伝達の一部は膜タンパク質Lgr6を介する (2016)
  • Author(s): 玉村 禎宏
  • Organizer: 第29回日本軟骨代謝学会
  • Place of Presentation: 応仁会館（広島県広島市南区霞）
  • Year and Date: 2016-02-19
• [Presentation] 軟骨発生および軟骨細胞分化における転写調節因子Irx3の役割 (2015)
  • Author(s): 玉村 禎宏
  • Organizer: 第57回歯科基礎医学会学術大会
  • Place of Presentation: 朱鷺メッセ（新潟県新潟市中央区万代島）
  • Year and Date: 2015-09-11
• [Presentation] 転写調節因子Irx3の初期軟骨細胞分化における役割について (2015)
  • Author(s): 玉村禎宏、目良恒、糸数万紀、脇谷滋之
  • Organizer: 第28回日本軟骨代謝学会
  • Place of Presentation: 東京医科歯科大学（東京都、文京区、湯島）
  • Year and Date: 2015-03-06 – 2015-03-07