title: 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.affiliation: Department of Orthopaedic Surgery, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Akune
authors.forename: Naoshi
authors.initials: N
authors.lastname: Ogata
authors.forename: Kazuto
authors.initials: K
authors.lastname: Hoshi
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tobe
authors.forename: Hideko
authors.initials: H
authors.lastname: Takagi
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Azuma
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Kozo
authors.initials: K
authors.lastname: Nakamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawaguchi
mesh_terms: D000818:Animals; D015415:Biomarkers; D001851:Bone Diseases, Metabolic / Q000473:pathology / Q000503:physiopathology; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D005269:Femur; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007378:Interleukins / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D053245:RANK Ligand; D011859:Radiography; D053246:Receptor Activator of Nuclear Factor-kappa B; D013977:Tibia / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology
chemical_list: D015415:Biomarkers; D002352:Carrier Proteins; D006023:Glycoproteins; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D007378:Interleukins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D008562:Membrane Glycoproteins; D010750:Phosphoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D007334:Insulin-Like Growth Factor I