High leptin concentrations and low SOCS-3 expression are associated with increased MMP levels in patients with osteoarthritis

K Vuolteenaho1, A Koskinen1, R Nieminen1, T Moilanen2, E Moilanen1. 1The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland, 2Coxa Hospital for Joint Replacement, Tampere, Finland

Background: Leptin is an adipokine regulating energy balance and appetite and it has recently been related also to arthritis as a proinflammatory factor. SOCS-3 (suppressor of cytokine signaling) acts as an intracellular negative feedback regulator in cytokine signalling and in hypothalamus mediating obesity related leptin resistance. In the present study, we measured the effects of leptin on MMP production in human OA cartilage, and further, investigated the association between SOCS-3 expression in cartilage and MMP concentrations in synovial fluid from osteoarthritis (OA) patients.

Methods: Synovial fluid and cartilage samples were obtained from 28 OA patients (19 females, BMI 32.3±1.3kg/m2, age 71±2 years; mean±SEM) undergoing total knee replacement surgery. SOCS-3 expression in cartilage samples was measured by Western blotting, and MMP-1 and MMP-3 concentrations in synovial fluid by ELISA. In addition, the effects of leptin on MMP production in cartilage were studied in tissue culture experiments.

Results: SOCS-3 expression in cartilage was significantly reduced in obese patients (BMI>30), while leptin concentrations in synovial fluid showed a positive correlation to BMI. Synovial fluid MMP-1 (r=-0.460, p=0.030) and MMP-3 (r=-0.426, p=0.030) concentrations correlated negatively to SOCS-3 expression in cartilage, implying importance of a SOCS-3 regulated factor in the pathogenesis of OA. In addition, leptin enhanced MMP-1 and MMP-3 production in human OA cartilage in vitro.

Conclusion: In obese OA patients (BMI>30) expression of inhibitory SOCS-3 in OA cartilage was low, while leptin concentrations were high. These changes were associated with increased levels of cartilage destructing MMPs in synovial fluid, and MMP production in cartilage was enhanced by leptin. These results support the idea of leptin as a factor linking obesity and OA, and as target for disease-modifying drugs for the treatment of OA.