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Published 14 October 2002. doi:10.1083/jcb.200204046
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© The Rockefeller University Press, 0021-9525/2002/10/147 $5.00
The Journal of Cell Biology, Volume 159, Number 1, 147-156

Article

Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts



Toru Akune1, Naoshi Ogata1, Kazuto Hoshi1, Naoto Kubota2, Yasuo Terauchi2, Kazuyuki Tobe2, Hideko Takagi3, Yoshiaki Azuma3, Takashi Kadowaki2, Kozo Nakamura1 and Hiroshi Kawaguchi1

1 Department of Orthopaedic Surgery, University of Tokyo, Tokyo 113-8655, Japan
2 Department of Metabolic Diseases, University of Tokyo, Tokyo 113-8655, Japan
3 Teijin Co. Ltd., Tokyo 191-8512, Japan

Address correspondence to Hiroshi Kawaguchi, M.D., Ph.D, Department of Orthopaedic Surgery, Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan. Tel.: 81-33815-5411, ext. 30473 or 33376. Fax: 81-33818-4082. E-mail: kawaguchi-ort{at}h.u-tokyo.ac.jp

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. Although mice lacking the IRS-2 gene (IRS-2-/- mice) developed normally, they exhibited osteopenia with decreased bone formation and increased bone resorption. Cultured IRS-2-/- osteoblasts showed reduced differentiation and matrix synthesis compared with wild-type osteoblasts. However, they showed increased receptor activator of nuclear factor {kappa}B ligand (RANKL) expression and osteoclastogenesis in the coculture with bone marrow cells, which were restored by reintroduction of IRS-2 using an adenovirus vector. Although IRS-2 was expressed and phosphorylated by insulin and IGF-I in both osteoblasts and osteoclastic cells, cultures in the absence of osteoblasts revealed that intrinsic IRS-2 signaling in osteoclastic cells was not important for their differentiation, function, or survival. It is concluded that IRS-2 deficiency in osteoblasts causes osteopenia through impaired anabolic function and enhanced supporting ability of osteoclastogenesis. We propose that IRS-2 is needed to maintain the predominance of bone formation over bone resorption, whereas IRS-1 maintains bone turnover, as we previously reported; the integration of these two signalings causes a potent bone anabolic action by insulin and IGF-I.

Key Words: insulin-like growth factor-I; osteoclast; osteoporosis; diabetes mellitus; cytokine


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