title: Abnormalities of insulin-like growth factor-I signaling and impaired cell proliferation in osteoblasts from subjects with osteoporosis.
abstract: IGF-I regulates bone acquisition and maintenance, even though the cellular targets and signaling pathways responsible for its action in human bone cells are poorly understood. Whether abnormalities in IGF-I action and signaling occur in human osteoblasts under conditions of net bone loss has not been determined. Herein we carried out a comparative analysis of IGF-I signaling in primary cultures of human osteoblasts from osteoporotic and control donors. In comparison with control cells, osteoporotic osteoblasts showed increased tyrosine phosphorylation of the IGF-I receptor in the basal state and blunted stimulation of receptor phosphorylation by IGF-I. Augmentation of basal IGF-I receptor phosphorylation was associated with coordinate increases in basal tyrosine phosphorylation of insulin receptor substrate (IRS)-2 and activation of Erk, which were also minimally responsive to IGF-I stimulation. By contrast, phosphorylation levels of IRS-1, Akt, and glycogen synthase kinase-3 were similar in the basal state in control and osteoporotic osteoblasts and showed marked increases after IGF-I stimulation in both cell populations, even though these responses were significantly lower in the osteoporotic osteoblasts. The IGF-I signaling abnormalities in osteoporotic osteoblasts were associated with reduced DNA synthesis both under basal conditions and after stimulation with IGF-I. Interestingly, treatment of the osteoporotic osteoblasts with the MAPK kinase inhibitor PD098059 reduced the elevated levels of Erk phosphorylation and increased basal DNA synthesis. Collectively, our data show that altered osteoblast proliferation in human osteoporosis may result from dysregulation of IGF-I receptor signaling, including constitutive activation of the IRS-2/Erk signaling pathway, which becomes unresponsive to IGF-I, and defective induction of the IRS-1/Akt signaling pathway.
authors: Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, and Metabolic Diseases, University of Bari, Piazza Giulio Cesare, 11, I-70124 Bari, Italy.
authors: Sebastio
authors: S
authors: Perrini
authors: Annalisa
authors: A
authors: Natalicchio
authors: Luigi
authors: L
authors: Laviola
authors: Angelo
authors: A
authors: Cignarelli
authors: Mariangela
authors: M
authors: Melchiorre
authors: Francesca
authors: F
authors: De Stefano
authors: Cristina
authors: C
authors: Caccioppoli
authors: Anna
authors: A
authors: Leonardini
authors: Sabina
authors: S
authors: Martemucci
authors: Gaetana
authors: G
authors: Belsanti
authors: Sara
authors: S
authors: Miccoli
authors: Anna
authors: A
authors: Ciampolillo
authors: Ada
authors: A
authors: Corrado
authors: Francesco Paolo
authors: FP
authors: Cantatore
authors: Riccardo
authors: R
authors: Giorgino
authors: Francesco
authors: F
authors: Giorgino
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010024:Osteoporosis / Q000378:metabolism / Q000503:physiopathology*; D010750:Phosphoproteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3