title: Impairment of bone healing by insulin receptor substrate-1 deficiency.
abstract: Insulin receptor substrate-1 (IRS-1) is an essential molecule for intracellular signaling of insulin-like growth factor (IGF)-I and insulin, both of which are potent anabolic regulators of bone and cartilage metabolism. To investigate the role of IRS-1 in bone regeneration, fracture was introduced in the tibia, and its healing was compared between wild-type (WT) mice and mice lacking the IRS-1 gene (IRS-1(-/-) mice). Among 15 IRS-1(-/-) mice, 12 remained in a non-union state even at 10 weeks after the operation, whereas all 15 WT mice showed a rigid bone union at 3 weeks. This impairment was because of the suppression of callus formation with a decrease in chondrocyte proliferation and increases in hypertrophic differentiation and apoptosis. Reintroduction of IRS-1 to the IRS-1(-/-) fractured site using an adenovirus vector significantly restored the callus formation. In the culture of chondrocytes isolated from the mouse growth plate, IRS-1(-/-) chondrocytes showed less mitogenic ability and Akt phosphorylation than WT chondrocytes. An Akt inhibitor decreased the IGF-I-stimulated DNA synthesis of chondrocytes more potently in the WT culture than in the IRS-1(-/-) culture. We therefore conclude that IRS-1 deficiency impairs bone healing at least partly by inhibiting chondrocyte proliferation through the phosphatidylinositol 3-kinase/Akt pathway, and we propose that IRS-1 can be a target molecule for bone regenerative medicine.
authors.affiliation: Departments of Orthopaedic Surgery, Tissue Engineering, and Metabolic Diseases, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo, Tokyo 113-8655, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimoaka
authors.forename: Satoru
authors.initials: S
authors.lastname: Kamekura
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Chikuda
authors.forename: Kazuto
authors.initials: K
authors.lastname: Hoshi
authors.forename: Ung-Il
authors.initials: UI
authors.lastname: Chung
authors.forename: Toru
authors.initials: T
authors.lastname: Akune
authors.forename: Zenjiro
authors.initials: Z
authors.lastname: Maruyama
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Komori
authors.forename: Michihiro
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Wataru
authors.initials: W
authors.lastname: Ogawa
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
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: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D015519:Bone Density; D001842:Bone and Bones / Q000378:metabolism*; D002455:Cell Division; D019902:Chondrocytes / Q000378:metabolism; D003094:Collagen / Q000235:genetics; D004247:DNA / Q000378:metabolism; D018014:Gene Transfer Techniques; D007150:Immunohistochemistry; D055504:Insulin Receptor Substrate Proteins; D007763:Lac Operon; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012038:Regeneration; D015398:Signal Transduction; D013997:Time Factors; D014945:Wound Healing; D014965:X-Rays
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D003094:Collagen; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases