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Molecular mechanism of bone-resorption in osteoclasts through microtubule regulation

Research Project

Project/Area Number 23659707
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Orthopaedic surgery
Research InstitutionThe University of Tokyo

Principal Investigator

TANAKA Sakae  東京大学, 医学部附属病院, 教授 (50282661)

Co-Investigator(Kenkyū-buntansha) KADONO Yuho  東京大学, 医学部附属病院, 講師 (70401065)
YASUI Tetsuro  東京大学, 医学部附属病院, 助教 (30583108)
Project Period (FY) 2011 – 2012
Project Status Completed (Fiscal Year 2012)
Budget Amount *help
¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2011: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Keywords骨 / 軟骨代謝学 / 破骨細胞 / 微小管 / AKT / Akt
Research Abstract

We investigated the role of Akt, a downstream effector of phosphatidylinositol 3-kinase, in bone-resorbing activity of mature osteoclasts. Treatment with a specific Akt inhibitor disrupted sealing zone formation and decreased the bone-resorbing activity of osteoclasts. The normal microtubule structures were lost and the Akt inhibitor reduced the amount of acetylated tubulin, which reflects stabilized microtubules, whereas forced Akt activation by adenovirus vectors resulted in the opposite effect. Forced Akt activation increased the binding of themicrotubule-associated protein APC, the APC-binding protein end-binding protein 1 (EB1) and dynactin, a dynein activator complex, with microtubules. Depletion of Akt1 and Akt2 resulted in a disconnection of APC/EB1 and a decrease in bone-resorbing activity along with reduced sealing zone formation, both of which were recovered upon the addition ofLiCl, a GSK-3ss inhibitor. The Akt1 and Akt2 double knock-out mice exhibitedosteosclerosis due to reduced bone resorption. These findings indicate that Akt controls the bone-resorbing activity of osteoclasts by stabilizing microtubules via a regulationof the binding of microtubule associated proteins.

Report

(3 results)
  • 2012 Annual Research Report   Final Research Report ( PDF )
  • 2011 Research-status Report
  • Research Products

    (4 results)

All 2013 2012 2011

All Journal Article (3 results) (of which Peer Reviewed: 3 results) Presentation (1 results)

  • [Journal Article] Regulation of bone resorption and sealing zone formation in osteoclasts occurs through protein kinase b-mediated microtubule stabilization2013

    • Author(s)
      Takumi Matsumoto
    • Journal Title

      J Bone Miner Res.

      Volume: 28 Issue: 5 Pages: 1191

    • DOI

      10.1002/jbmr.1844

    • Related Report
      2012 Annual Research Report 2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] 4. Regulation of bone destruction in rheumatoid arthritis through RANKL-RANK pathways.2013

    • Author(s)
      Sakae Tanaka
    • Journal Title

      World J Orthop.

      Volume: 4 Issue: 1 Pages: 1-6

    • DOI

      10.5312/wjo.v4.i1.1

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Distinguishing the proapoptotic and antiresorptive functions of risedronate in murine osteoclasts: Role of the akt pathway and the ERK/Bim axis2011

    • Author(s)
      Matsumoto T, Nagase Y, Iwasawa M, Yasui T, Masuda H, Kadono Y, Nakamura K, Tanaka S
    • Journal Title

      Arthritis and Rheumatism

      Volume: 63 Issue: 12 Pages: 3908

    • DOI

      10.1002/art.30646

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Presentation] Regulation of bone resorption and sealing zone formation in osteoclasts occurs through protein kinase b-mediated microtubule stabilization2012

    • Author(s)
      Tanaka S, Tokuyama N, Matsumoto T, Kadono Y
    • Organizer
      Annual Meeting of the American Society for Bone and Mineral Research
    • Place of Presentation
      Minneapolis, Minnesota, USA
    • Related Report
      2012 Final Research Report

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Published: 2011-08-05   Modified: 2019-07-29  

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