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

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. 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 kappaB 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.
Authors	Toru Akune, Naoshi Ogata, Kazuto Hoshi, Naoto Kubota, Yasuo Terauchi, Kazuyuki Tobe, Hideko Takagi, Yoshiaki Azuma, Takashi Kadowaki, Kozo Nakamura, Hiroshi Kawaguchi
Journal	The Journal of cell biology (J Cell Biol) Vol. 159 Issue 1 Pg. 147-56 (Oct 14 2002) ISSN: 0021-9525 [Print] United States
PMID	12379806 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Biomarkers Carrier Proteins Glycoproteins IRS1 protein, human IRS2 protein, human Insulin Insulin Receptor Substrate Proteins Interleukins Intracellular Signaling Peptides and Proteins Irs1 protein, mouse Irs2 protein, mouse Membrane Glycoproteins Phosphoproteins RANK Ligand Receptor Activator of Nuclear Factor-kappa B TNFRSF11A protein, human TNFSF11 protein, human Tnfrsf11a protein, mouse Tnfsf11 protein, mouse Insulin-Like Growth Factor I
Topics	Animals Biomarkers Bone Diseases, Metabolic (pathology, physiopathology) Bone Marrow Cells (cytology, metabolism) Carrier Proteins (genetics, metabolism) Cell Differentiation (physiology) Cells, Cultured Coculture Techniques Female Femur Glycoproteins (metabolism) Humans Insulin (pharmacology) Insulin Receptor Substrate Proteins Insulin-Like Growth Factor I (metabolism) Interleukins (pharmacology) Intracellular Signaling Peptides and Proteins Male Membrane Glycoproteins (genetics, metabolism) Mice Mice, Knockout Osteoblasts (cytology, drug effects, metabolism) Osteoclasts (metabolism) Phosphoproteins (genetics, metabolism) RANK Ligand Radiography Receptor Activator of Nuclear Factor-kappa B Tibia (diagnostic imaging, metabolism, pathology)

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