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

• Published in: Endocrinology (Philadelphia) 2005-06, Vol.146 (6), p.2620-2628
• Main Authors: Yamaguchi, Masayuki, Ogata, Naoshi, Shinoda, Yusuke, Akune, Toru, Kamekura, Satoru, Terauchi, Yasuo, Kadowaki, Takashi, Hoshi, Kazuto, Chung, Ung-Il, Nakamura, Kozo, Kawaguchi, Hiroshi
• Format: Article
• Language: English
• Subjects: Adaptor proteins; Alkaline phosphatase; Animals; Autocrine signalling; Biological and medical sciences; Biomarkers; Bone and Bones - cytology; Bone and Bones - drug effects; Bone and Bones - metabolism; Bone Density - drug effects; Bone Density - physiology; Bone growth; Bone turnover; Bones; Cells, Cultured; Female; Femur; Fundamental and applied biological sciences. Psychology; Insulin; Insulin receptor substrate 1; Insulin Receptor Substrate Proteins; Insulin receptors; Insulin-like growth factor I; Intracellular Signaling Peptides and Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Molecular modelling; mRNA; Osteoblasts; Osteoblasts - cytology; Osteoblasts - metabolism; Osteogenesis; Paracrine signalling; Parathyroid hormone; Parathyroid Hormone - metabolism; Parathyroid Hormone - pharmacology; Peptide Fragments - metabolism; Peptide Fragments - pharmacology; Phosphoproteins - genetics; Phosphoproteins - metabolism; Receptors; Skeleton and joints; Tibia; Vertebrae; Vertebrates: osteoarticular system, musculoskeletal system
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2004-1511

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.