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01 November 2006

Leptin increases proliferation of human osteosarcoma cells through activation of PI(3)-K and MAPK pathways

Bartolome Burguera, Amy Brunetto, Adolfo Garcia-Ocana, Roseta Teijeiro, James Esplen, Thierry Thomas, Marta E. Couce, Allan Zhao

Med Sci Monit 2006; 12(11): BR341-349 :: ID: 462552

Abstract

Background: Serum leptin levels are strongly and directly related to fat body mass (FBM). Bone mineral density(BMD) increases with FBM, and obesity has a protective effect against osteoporosis. We have previously demonstrated that leptin therapy has a signifi cant effect in preventing ovariectomy-induced
bone loss in rats and leptin also exerts direct osteogenic effects in vitro. To obtain a better understanding of the physiology and pharmacology of leptin in bone metabolism, we evaluated the leptin-induced signal transduction pathways and proliferative response in the human osteosarcoma cell line Saos-2.
Material/Methods: Saos-2 cell lines were used. Leptin receptor common form (OB-Ra) and long form (OB-Rb) were detected by RT-PCR and immunocytochemistry. PI(3)-K activity was immunoprecipitated using antibodies
directed against tyrosine-phosphorylated proteins and IRS-1. The activated form of p42/p44 MAPK was investigated in cytosolic extracts of confl uent Saos-2 in response to leptin.
Results: In this study, we tested the hypothesis that leptin might be a mediator linking obesity and bone
cell proliferation. We found that Saos-2 cells expressed OB-Ra and OB-Rb. Leptin (10 nmol/L –
2 umol/L) caused a signifi cant increase in the activation of PI(3)-K that was accompanied by an
increase in cell proliferation dose dependently based on the [[sup]3[/sup]H]-thymidine incorporation. The
specifi c PI(3)-K inhibitors LY294002 and wortmannin blocked leptin-induced cell proliferation.
Interestingly, leptin activated MAPK and the specifi c MAPK-inhibitor PD98059 blocked DNA synthesis
induced by leptin.
Conclusions: Our data support the hypothesis that leptin may increase bone mass by stimulating osteoblast proliferation through activation of the PI(3)-K and MAPK signaling pathways.

Keywords: Cell Line, Tumor, Bone and Bones - metabolism, Enzyme Activation, Enzyme Inhibitors - pharmacology, Insulin Receptor Substrate Proteins, Leptin - physiology, MAP Kinase Signaling System, Osteosarcoma - pathology, Phosphatidylinositol 3-Kinases - metabolism, Phosphoproteins - metabolism, Phosphorylation, Signal Transduction, Tyrosine - chemistry

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