Our results indicated using two different sets of primers for RT-PCR experiments that leptin was expressed only in Obs not in chondrocytes. The expression of leptin was also higher in OA Obs compared with normal using real-time PCR and was responsible for the increase in leptin levels noted in conditioned-media from OA Obs. Although leptin was not expressed by chondrocytes, it was present in articular cartilage – suggesting that leptin produced in bone tissue reached the overlaying cartilage. The long-form leptin receptor mRNA levels were slightly reduced in OA Obs compared with normal Obs. Since leptin can promote the differentiation of Obs, we next questioned whether the observed increase in alkaline phosphatase activity (ALP) and osteocalcin release (OC) observed in OA Obs was linked with their endogenous leptin production. Inactivating antibodies against the leptin receptor reduced both ALP and OC in OA Obs about 35%, a situation reproduced with Tyr and Pce. Likewise, Tyr and Pce also reduced ALP, CICP release, and TGFβ1 production in OA Obs. Last, leptin dose-dependently (1 ng/ml to 10 mg/ml) stimulated cellular proliferation in OA Obs and this was reflected by an increase in phosphorylation of Erk1/2 signaling.