Background/Purpose: Leptin is an adipokine whose concentrations in circulation are proportional to body fat stores and body mass index (BMI). Initially leptin was discovered to regulate energy metabolism and body weight. More recently it has been recognized as effector and regulator in inflammation and arthritis. Leptin has been shown to have detrimental effects on cartilage metabolism including upregulation of proinflammatory and catabolic factors.

Suppressor of cytokine signaling 3 (SOCS-3) is an intracellular regulator of inflammatory response and a negative regulator of leptin’s effects in hypothalamus. It has also been shown to be expressed in chondrocytes and overexpression of SOCS-3 has been reported to reduce severity of arthritis in mice models.

The aim of the present study was to explore how SOCS-3 expression in osteoarthritic (OA) cartilage is related to obesity and synovial fluid levels of matrix metalloproteinases (MMPs) 1 and 3 and leptin in OA patients. We also studied the role of SOCS-3 in regulating leptin-induced inflammatory responses in chondrocyte cultures.

Methods: We collected synovial fluid and cartilage samples from 91 OA patients [age 70.2 (9.6) years, BMI 30.8 (5.8) kg/m²; mean (sd); females 66%] undergoing knee replacement surgery. Leptin, MMP-1 and MMP-3 in synoval fluid were measured by immunoassay. SOCS-3 expression in cartilage (from a subgroup of the patients, n = 28) was determined by Western blotting. The results were analyzed in the whole group and in two subroups divided by BMI (non-obese, BMI < 30 kg/m², n = 45; obese, BMI > 30 kg/m², n = 46). In addition, H4 chondrocytes and OA cartilage were used in the cell culture experiments. Interleukin-6 (IL-6), MMP-1 and MMP-3 were measured in the culture media by ELISA, and inducible nitric oxide synthase (iNOS) expression was determined by RT-PCR and Western blotting.

Results: Leptin concentrations in synovial fluid were higher (p < 0.001) and SOCS-3 expression in cartilage samples was lower (p = 0.032) in obese than in non-obese patients. Leptin correlated positively with MMP-1 and MMP-3 levels in synovial fluid from obese (r = 0.49, p = 0.001; r = 0.48, p = 0.001, respectively) but not from non-obese patients. SOCS-3 levels in the cartilage correlated negatively with synovial fluid MMP-1 and MMP-3 (r=-0.49, p=0.013; r=-0.44, p=0.024, respectively). Leptin enhanced MMP-1, MMP-3, IL-6 and iNOS expression in chondrocyte cultures. Interestingly, when SOCS-3 was down-regulated by small interfering RNA, chondrocytes’ response to leptin was enhanced.

Conclusion: The results show, for the first time, that SOCS-3 is associated with and regulates leptin-induced responses in cartilage; When SOCS-3 expression was down-regulated, leptin-induced effects were enhanced. In OA patients high leptin levels and low SOCS-3 levels were associated with cartilage degradation (high MMP levels) and obesity. Assuming that SOCS-3 is a factor that inhibits the effects of leptin in cartilage, obese patients are possibly more susceptible to detrimental effects of leptin not only because of its elevated levels in joint, but also because of the disturbed regulation mechanism.

---

« Back to 2012 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/suppressor-of-cytokine-signaling-3-is-reduced-in-obese-patients-with-osteoarthritis-and-regulates-leptin-responses-in-chondrocytes/