title: Skeletal unloading-induced insulin-like growth factor 1 (IGF-1) nonresponsiveness is not shared by platelet-derived growth factor: the selective role of integrins in IGF-1 signaling.
abstract: Integrin receptors bind extracellular matrix proteins, and this link between the cell membrane and the surrounding matrix may translate skeletal loading to biologic activity in osteoprogenitor cells. The interaction between integrin and growth factor receptors allows for mechanically induced regulation of growth factor signaling. Skeletal unloading leads to decreased bone formation and osteoblast proliferation that can be explained in part by a failure of insulin-like growth factor 1 (IGF-1) to activate its signaling pathways in unloaded bone. The aim of this study is to determine whether unloading-induced resistance is specific for IGF-1 or common to other skeletal growth factors, and to examine the regulatory role of integrins in IGF-1 signaling. Bone marrow osteoprogenitor (BMOp) cells were isolated from control or hindlimb suspended rats. Unloaded BMOp cells treated with IGF-1 failed to respond with increased proliferation, receptor phosphorylation, or signaling activation in the setting of intact ligand binding, whereas the platelet-derived growth factor (PDGF) response was fully intact. Pretreatment of control BMOp cells with an integrin inhibitor, echistatin, failed to disrupt PDGF signaling but blocked IGF-1 signaling. Recovery of IGF-1 signaling in unloaded BMOp cells followed the recovery of marked reduction in integrin expression induced by skeletal unloading. Selective targeting of integrin subunits with siRNA oligonucleotides revealed that integrin β1 and β3 are required for normal IGF-1 receptor phosphorylation. We conclude that integrins, in particular integrin β3, are regulators of IGF-1, but not PDGF, signaling in osteoblasts, suggesting that PDGF could be considered for investigation in prevention and/or treatment of bone loss during immobilization and other forms of skeletal unloading.
authors.affiliation: Department of Medicine, University of California, Davis, CA, USA. roger.long@ucdmc.ucdavis.edu
authors.forename: Roger K
authors.initials: RK
authors.lastname: Long
authors.forename: Shigeki
authors.initials: S
authors.lastname: Nishida
authors.forename: Takuo
authors.initials: T
authors.lastname: Kubota
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Wang
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakata
authors.forename: Hashem Z
authors.initials: HZ
authors.lastname: Elalieh
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Halloran
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Bikle
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D019417:Hindlimb Suspension; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008297:Male; D010455:Peptides / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D019012:Integrin beta1; D039661:Integrin beta3; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D010455:Peptides; D010982:Platelet-Derived Growth Factor; D021122:Protein Subunits; C057986:echistatin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1