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J. Biol. Chem., Vol. 279, Issue 15, 15314-15322, April 9, 2004

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Impairment of Bone Healing by Insulin Receptor Substrate-1 Deficiency^*

Takashi Shimoaka, Satoru Kamekura, Hirotaka Chikuda, Kazuto Hoshi, Ung-il Chung, Toru Akune, Zenjiro Maruyama¶, Toshihisa Komori¶, Michihiro Matsumoto||, Wataru Ogawa||, Yasuo Terauchi**, Takashi Kadowaki**, Kozo Nakamura, and Hiroshi Kawaguchi

From the Departments of Orthopaedic Surgery, Tissue Engineering, and ^**Metabolic Diseases, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo, Tokyo 113-8655, ^¶Department of Molecular Medicine, Osaka University Medical School, Suita, Osaka 565-0871, and ^||Division of Diabetes, Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan

Insulin receptor substrate-1 (IRS-1) is an essential molecule for intracellular signaling of insulin-like growth factor (IGF)-I and insulin, both of which are potent anabolic regulators of bone and cartilage metabolism. To investigate the role of IRS-1 in bone regeneration, fracture was introduced in the tibia, and its healing was compared between wild-type (WT) mice and mice lacking the IRS-1 gene (IRS-1^-/- mice). Among 15 IRS-1^-/- mice, 12 remained in a non-union state even at 10 weeks after the operation, whereas all 15 WT mice showed a rigid bone union at 3 weeks. This impairment was because of the suppression of callus formation with a decrease in chondrocyte proliferation and increases in hypertrophic differentiation and apoptosis. Reintroduction of IRS-1 to the IRS-1^-/- fractured site using an adenovirus vector significantly restored the callus formation. In the culture of chondrocytes isolated from the mouse growth plate, IRS-1^-/- chondrocytes showed less mitogenic ability and Akt phosphorylation than WT chondrocytes. An Akt inhibitor decreased the IGF-I-stimulated DNA synthesis of chondrocytes more potently in the WT culture than in the IRS-1^-/- culture. We therefore conclude that IRS-1 deficiency impairs bone healing at least partly by inhibiting chondrocyte proliferation through the phosphatidylinositol 3-kinase/Akt pathway, and we propose that IRS-1 can be a target molecule for bone regenerative medicine.

Received for publication, November 16, 2003 , and in revised form, January 15, 2004.

^* This work was supported by Grants-in-aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology 11470301 and 12137201, the Uehara Memorial Foundation, and the Takeda Science Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Orthopaedic Surgery, Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo, Tokyo 113-8655, Japan. Tel.: 81-3-3815-5411 (ext. 30473 or 33376); Fax: 81-3-3818-4082; E-mail: kawaguchi-ort{at}h.u-tokyo.ac.jp.

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