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Med Sci Monit. 2006 Nov;12(11):BR341-9.

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

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1
Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. bburguera@hsd.es

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 significant 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 confluent 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 significant increase in the activation of PI (3)-K that was accompanied by an increase in cell proliferation dose dependently based on the [3H]-thymidine incorporation. The specific PI (3)-K inhibitors LY294002 and wortmannin blocked leptin-induced cell proliferation. Interestingly, leptin activated MAPK and the specific 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 P1 (3)-K and MAPK signaling pathways.

PMID:
17072262
[Indexed for MEDLINE]
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