Involvement in bone metabolism of Notch signaling regulated by ADAM10

• Project/Area Number: 23592230
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Keio University
• Principal Investigator: YODA MASAKI 慶應義塾大学, 医学部, 特任助教 (30464994)
• Co-Investigator(Kenkyū-buntansha): HORIUCHI Keisuke 慶應義塾大学, 医学部, 特任准教授 (30327564)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ADAM10 / Notch / 骨代謝 / shedding / 造血 / シェディング / シグナル伝達 / 発生・分化 / 免疫学

Research Abstract

ADAM10 is considered to be essential for the activation of Notch signaling. In this study, we generated mutant mice in which Adam10 is disrupted under the control of an inducible Mx1-Cre transgene (A10/Mx1 mice) and aimed to elucidate the potential functions of ADAM10-Notch signaling in bone metabolism. A10/Mx1 mice exhibited the increase in population of Gr-1+CD11b+ cells and hematopoietic stem cells. Furthermore, lack of ADAM10 in the non-hematopoietic cells lead to aberrant production of G-CSF. These results revealed that ADAM10-Notch signaling negatively regulates the production of G-CSF in non-hematopoietic cells and indirectly suppresses myelopoiesis in a non-cell-autonomous manner. On the other hand, A10/Mx1 mice exhibited an increase of osteoclast progenitor cells in the bone marrow, and many osteocalcin+ cells, a marker for mature osteoblast, existed on the trabecular bone. This result suggests A10/Mx1 mice accelerated not only bone resorption but also bone formation.

Research Products

• [Journal Article] Conditional inactivation of TNFα-converting enzyme in chondrocytes results in an elongated growth plate and shorter long bones (2013)
  • Author(s): Saito K, Horiuchi K, Kimura T, Mizuno S, Yoda M, Morioka H, Akiyama H, Threadgill D, Okada Y, Toyama Y, Sato K
  • Journal Title: PLoS One Volume: 8(1) Issue: 1 Pages: e54853-e54853
  • DOI: 10.1371/journal.pone.0054853
  • Peer Reviewed
• [Journal Article] Systemic overexpression of TNFα-converting enzyme does not lead to enhanced shedding activity in vivo (2013)
  • Author(s): Yoda M, Kimura T, Tohmonda T, Morioka H, Matsumoto M, Okada Y, Toyama Y, Horiuchi K
  • Journal Title: PLoS One Volume: 8(1) Issue: 1 Pages: e54412-e54412
  • DOI: 10.1371/journal.pone.0054412
  • Peer Reviewed
• [Journal Article] Dual functions of cell-autonomous and non-cell-autonomous ADAM10 activity in granulopoiesis (2011)
  • Author(s): Yoda M, Kimura T, Tohmonda T, Uchikawa S, Koba T, Takito J, Morioka H, Matsumoto M, Link DC, Chiba K, Okada Y, Toyama Y, Horiuchi K
  • Journal Title: Blood Volume: 118(26) Issue: 26 Pages: 6939-42
  • DOI: 10.1182/blood-2011-06-357210
  • Peer Reviewed
• [Presentation] ADAM10-Notchシグナル伝達を介した骨髄系細胞分化はG-CSF依存的および非依存的な経路によって制御されている (2012)
  • Author(s): 依田昌樹,戸山芳昭,堀内圭輔
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] ADAM10-Notch signaling regulates granulopoiesis via G-CSF-dependent and -independent manners (2012)
  • Author(s): Masaki Yoda, Yoshiaki Toyama, Keisuke Horiuchi
  • Organizer: 第35回 日本分子生物学会
  • Place of Presentation: 福岡国際会議場、マリンメッセ福岡
• [Remarks] 慶應義塾大学医学部整形外科学教室 基礎研究グループ 分子骨代謝
  • URL: http://www.keio-ortho.jp/orthopaedic/group05_03.html