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2005 Fiscal Year Final Research Report Summary

Elucidation of molecular mechanisms of osteoclastogenesis and its application for bone disease therapy

Research Project

Project/Area Number 16390428
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Orthopaedic surgery
Research InstitutionThe University of Tokyo

Principal Investigator

INOUE Jun-ichiro  The University of Tokyo, Institute of Medical Science, Professor, 医科学研究所, 教授 (70176428)

Co-Investigator(Kenkyū-buntansha) GOHDA Jin  The University of Tokyo, Institute of Medical Science, Assistant Professor, 医科学研究所, 助手 (90361617)
Project Period (FY) 2004 – 2005
KeywordsRANK / CD40 / TRAF6 / osteoclast / NFAT
Research Abstract

RANK and CD40 activate NF-kB and MAPKs to similar levels via TRAF6. Even though overexpression of TRAF6 results in osteoclast formation, RANK but not CD40 promotes osteoclastogenesis. To understand the molecular basis for RANK-specific activity in osteoclastogenesis, we created an osteoclast formation system driven by antihuman CD40 antibody-mediated stimulation of a chimeric receptor, h40/mRK, which consists of the extra cellular domain of human CD40 and the transmembrane and cytoplasmic domains of mouse RANK. By introducing mutations into three TRAF6-binding sites of RANK, we found that h40/mRK with a single TRAF6-binding site efficiently induced Ca2+ oscillation and expression of NFATc1, a master switch in osteoclastogenesis, whereas CD40 carrying a single TRAF6-binding site did not. However, expression of CD40 that was approximately 100 times greater than that of h40/mRK resulted in osteoclast formation, indicating that the RANK-TRAF6 signal is more potent than the CD40-TRAF6 signal in terms of NFATc1 activation and osteoclastogenesis. These results suggest that RANK may harbor a specific domain that amplifies TRAF6 signaling. To identify the specific domain, we have introduced various deletion into the cytoplasmic domain of RANK. We found a deletion mutant that can activate NF-kB and MAPKs but can not generate ostesoclasts. The domain missing in this mutant is highly conserved among various species, suggesting that the domain could be critical in TRAF6 activation required for osteoclastogenesis. We are currently focusing on this domain.

  • Research Products

    (2 results)

All 2005

All Journal Article (2 results)

  • [Journal Article] RANK-mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis2005

    • Author(s)
      Gohda, J, et al.
    • Journal Title

      EMBO J 24

      Pages: 790-799

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] RANK-mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis.2005

    • Author(s)
      Gohda, J., Akiyama, T., Koga, T., Takayanagi, H., Tanaka, S., Inoue, J.
    • Journal Title

      EMBO J 24

      Pages: 790-799

    • Description
      「研究成果報告書概要(欧文)」より

URL: 

Published: 2007-12-13  

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