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Mechanism of regulation of bone metabolism by insulin receptor substrates (IRS-1 and IRS-2)

Research Project

Project/Area Number 11470301
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

KONO Shinjiro (2001)  Faculty of Medicine, The University of Tokyo, Assistant, 医学部・附属病院, 助手 (40333463)

東 成一 (2000)  東京大学, 医学部・附属病院, 助手 (70313137)

小崎 慶介 (1999)  東京大学, 医学部・附属病院, 助手 (60302692)

Co-Investigator(Kenkyū-buntansha) TOBE Kazuyuki  Faculty of Medicine, The University of Tokyo, Assistant, 医学部・附属病院, 助手 (30251242)
NAKAMURA Kozo  Faculty of Medicine, The University of Tokyo, Professor, 医学部・附属病院, 教授 (60126133)
KAWAGUCHI Hiroshi  Faculty of Medicine, The University of Tokyo, Assistant Professor, 医学部・附属病院, 講師 (40282660)
小林 篤樹  東京大学, 医学部・附属病院, 助手
河野 慎次郎  東京大学, 医学部・附属病院, 助手
東 成一  東京大学, 医学部・附属病院, 助手
門脇 孝  東京大学, 医学部・附属病院, 講師 (30185889)
Project Period (FY) 1999 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥12,400,000 (Direct Cost: ¥12,400,000)
Fiscal Year 2001: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 2000: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1999: ¥6,700,000 (Direct Cost: ¥6,700,000)
Keywordsinsulin / IGF / bone / osteoporosis / IRS / osteoblast / 骨粗鬆症 / 骨折 / 骨再生 / 骨芽細胞 / 破骨細胞 / IRS-1,-2 / IGF-I
Research Abstract

Insulin receptor substrates (IRS-1 and IRS-2) are essential for intracellular signaling by insulin and insulin-like growth factor-I (IGF-I) , anabolic regulators of bone metabolism. To investigate the physiological roles of IRS-1 and IRS-2, weinvestigated the bone tissue of mice lacking IRS-1 or IRS-2 in vivo and in vitro. Mice lacking the IRS-1 gene (IRS-1^<-・-> mice) showed low-turnover osteopenia with the decrease in both bone formation and resorption. This was due to the impairment of the anabolic function and RANKL induction in osteoblasts. IRS-1^<-・-> mice also showed the impairment of the fracture healing ability by inhibiting the proliferation of mesenchymal cells and chondrocytes, suggesting that IRS-1 is essential for bone repair. On the other hand, IRS-2^<-・-> mice showed osteopenia with decreased bone formation and increased bone resorption. This was due to the impaired anabolic function and enhanced RANKL expression in osteoblasts. We propose that these anabolic actions are maintained as an integration of two proteins that have distinct biological roles in osteoblasts: IRS-1 and IRS-2. The former is essential to maintain bone turnover by up-regulating anabolic function and RANKL expression, while the latter is needed to keep the predominance of the anabolic function over the catabolic function.

Report

(4 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • Research Products

    (14 results)

All Other

All Publications (14 results)

  • [Publications] Naoshi Ogata: "Insulin receptor substrate-1 in osteoblast is independsable for maintaining bone turnover"J. Clin. Invest. 105. 935-943 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Toru Akune: "Insulin secretory response is positively associated with the extent of the ossification of the posterior longitudinal ligament of the spine"J. Bone Joint Surg (Am). 83. 1537-1544 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Naoshi Ogata, Daichi Chikazu, Naoto Kubota, Yasuo Terauchi, Kazuyuki Tobe, Yoshiaki Azuma, Tomohiro Ohta, Takashi Kadowaki, Kozo Nakamura, ajid Hiroshi Kawaguchi: "insulin receptor substrate-1 in osteoblast is indispensable for maintaining bone turnover"J Clin Invest. 105. 935-943 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Aotru Akune, Naoshi Ogata, Atsushi Scichi, Isao Ohnishi, Kozo Nakamura, and Hiroshi Kawaguchi: "Insulin secretory response is positively associated with the extent of ossification of the posterior longitudinal ligament of the spine"J Bone Joint Surg (Am). 83. 1537-1544 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Toru Akune: "Insulin secvetory response is positively asscciated with the extent of ossification of the posterior longitudinal ligament of the spire"Journal of Bone and Joint Surgery (Am). 83. 1537-1544 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 川口 浩: "インスリン/IGF情報伝達系による骨代謝の制御"新・分子骨代謝学と骨粗鬆症. 255-261 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 緒方直史, 川口 浩: "IRS-1遺伝子欠損マウスの骨代謝"The BONE. 15(7). 323-331 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 川口 浩: "インスリンシグナルと骨形成"The BONE. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Naoshi Ogata, et al.: "Insulin receptor substrate-1 in osteoblast is indispensable for maintaining bone turnover."J.Clin,Invest.. 105. 935-943 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Toru Akune, et al.: "Insulin secretory response is positively associated with the extent of the ossification of the posterior longitudinal ligoi of the spice"J.Bone Joint Surg. (Am). (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] 川口浩: "インスリン受容体基質-1ノックアウトマウスの解析"クリニシアン. 490. 413-416 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 緒方直史,川口浩: "IRS-1遺伝子欠損マウスの骨代謝"The Bone. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] 川口浩: "インスリン/IGF情報伝達系による骨代謝の制御"松本俊夫 編/メディカルレビュー社(in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] 緒方直史、川口浩、戸辺一之、門脇孝、中村耕三ら: "Insulin receptor substrate-1 in osteoblast is indispensable to maintain bone turnover"Journal of Clinical Investigation. (in press).

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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