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Insulin Receptor Substrate-1 Is Required for Bone Anabolic Function of Parathyroid Hormone in Mice

Departments of Sensory and Motor System Medicine (M.Y., N.O., Y.S., T.A., S.K., K.H., U.-I.C., K.N., H.K.) and Metabolic Diseases (Y.T., T.K.), Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan

Address all correspondence and requests for reprints to: Hiroshi Kawaguchi, M.D., Ph.D., Department of Sensory and Motor System Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: kawaguchi-ort{at}h.u-tokyo.ac.jp.

Bone anabolic action of PTH has been suggested to be mediated by induction of IGF-I in osteoblasts; however, little is known about the molecular mechanism by which IGF-I leads to bone formation under the PTH stimulation. This study initially confirmed in mouse osteoblast cultures that PTH treatment increased IGF-I mRNA and protein levels and alkaline phosphatase activity, which were accompanied by phosphorylations of IGF-I receptor, insulin receptor substrate (IRS)-1 and IRS-2, essential adaptor molecules for the IGF-I signaling. To learn the involvement of IRS-1 and IRS-2 in the bone anabolic action of PTH in vivo, IRS-1–/– and IRS-2–/– mice and their respective wild-type littermates were given daily injections of PTH (80 µg/kg) or vehicle for 4 wk. In the wild-type mice, the PTH injection increased bone mineral densities of the femur, tibia, and vertebrae by 10–20% without altering the serum IGF-I level. These stimulations were similarly seen in IRS-2–/– mice; however, they were markedly suppressed in IRS-1–/– mice. Although the PTH anabolic effects were stronger on trabecular bones than on cortical bones, the stimulations on both bones were blocked in IRS-1–/– mice but not in IRS-2–/– mice. Histomorphometric and biochemical analyses showed an increased bone turnover by PTH, which was also blunted by the IRS-1 deficiency, though not by the IRS-2 deficiency. These results indicate that the PTH bone anabolic action is mediated by the activation of IRS-1, but not IRS-2, as a downstream signaling of IGF-I that acts locally as an autocrine/paracrine factor.

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