Abstract
BackgroundPrevious studies provide evidence that adipokine leptin increases production of catabolic and proinflammatory factors in chondrocytes and serves as a link between obesity and osteoarthritis (OA). However, the magnitude of the response to leptin treatment varies greatly between chondrocytes from different donor patients. In the present study, we investigated the regulatory role of suppressor of cytokine signaling-3 (SOCS-3) in the leptin-induced responses in OA cartilage.MethodsCartilage and synovial fluid samples from 97 patients with OA undergoing knee replacement surgery were collected. Cartilage samples were cultured with leptin (10 μg/ml), and the levels of proinflammatory and catabolic factors in synovial fluid and in the cartilage culture media, and SOCS-3 expression in the cartilage were measured. The role of SOCS-3 in leptin signaling was further studied in H4 murine chondrocytes by downregulating SOCS-3 with siRNA.ResultsLeptin-induced expression of matrix metalloproteinases MMP-1, MMP-3, MMP-13, interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were higher in the cartilage samples with low SOCS-3 expression. Accordingly, downregulation of SOCS-3 by siRNA in H4 chondrocytes led to enhanced leptin-induced expression of MMP-3, MMP-13, IL-6 and iNOS. Synovial fluid leptin was associated positively, and cartilage SOCS-3 negatively with synovial fluid levels of MMPs in a multivariate model in obese (body mass index (BMI) >30 kg/m2) but not in non-obese (BMI <30 kg/m2) patients.ConclusionsOur results show, for the first time, that SOCS-3 regulates leptin-induced responses in cartilage, and could thus be a future drug target in the treatment or prevention of OA, especially in obese patients.
Highlights
Previous studies provide evidence that adipokine leptin increases production of catabolic and proinflammatory factors in chondrocytes and serves as a link between obesity and osteoarthritis (OA)
Leptin significantly enhanced the expression of matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, IL-6, inducible nitric oxide synthase (iNOS) and COX-2 and nitric oxide (NO) production in OA cartilage ex vivo (Fig. 1)
When the patients were divided into subgroups according to suppressor of cytokine signaling-3 (SOCS-3) expression in the cartilage, leptin-induced changes in the expression/production of matrix metalloproteinase 1 (MMP-1), MMP-3, MMP-13, IL-6, NO, iNOS and COX-2 in the cartilage were significantly greater in the samples with low SOCS-3 expression than in the samples with high SOCS-3 expression (Fig. 2)
Summary
Previous studies provide evidence that adipokine leptin increases production of catabolic and proinflammatory factors in chondrocytes and serves as a link between obesity and osteoarthritis (OA). We investigated the regulatory role of suppressor of cytokine signaling-3 (SOCS-3) in the leptin-induced responses in OA cartilage. Adipokines are cytokine-like hormones produced by adipose tissue and originally discovered to regulate energy metabolism [1, 2]. Their role in inflammation and obesity-related disease, such as type 2 diabetes mellitus and cardiovascular disease, and in rheumatic disease has attracted increasing interest during the past decade. Obesity is a major risk factor for OA [9]. Obesity is a risk factor for hand OA
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