Background/Purpose: Adipocytokine leptin has been suggested to link obesity and osteoarthritis (OA). Initially leptin was found to regulate energy metabolism through central nervous system. More recent studies have shown that leptin is also a proinflammatory factor in arthritis and has detrimental effects on cartilage including upregulation of proinflammatory and catabolic factors. However, we and others have found a significant variation in the leptin responses in cartilage samples between different donor patients. One of the factors that regulate the metabolic effects of leptin in hypothalamus is suppressor of cytokine signaling 3 (SOCS-3). SOCS-3 is also known as an important negative feedback mechanism of inflammatory signals in leukocytes. The aim of the present study was to investigate SOCS-3 as a possible modulator of leptin’s detrimental effects in cartilage.

Methods: Cartilage samples from 97 OA patients undergoing knee replacement surgery were collected. Cartilage explants were cultured with leptin (10 µg/ml) for 42 hours. The expression of SOCS-3, inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 were measured by Western blotting. Matrix metalloproteinase (MMP)-1, MMP-3 and IL-6 were measured in the culture media by ELISA, and nitric oxide (NO) by the Griess reaction. The results were analyzed in an ANOVA model allowing for intergel variation of SOCS-3, and adjusting for BMI and age. The role of SOCS-3 in leptin signaling was further studied in H4 chondrocytes by downregulating SOCS-3 with siRNA.

Results: Leptin significantly enhanced the expression of NO, IL-6, MMP-1, MMP-3, iNOS and COX-2 in the cultured cartilage samples (fold of increase: 2.7 (6.2); 8.3 (30.5); 2.8 (3.4); 1.8 (1.2); 11.7 (160); 6.9 (18); median (IQR), respectively). There was a considerable variation in these responses between the cartilage samples from different donor patients, which was not explained by any clinical factor measured (BMI, age, sex, diabetic status, radiographic scaling of OA or macroscopic scaling of cartilage defects). Leptin responses were significantly higher in the cartilage samples with low SOCS-3 expression than in the samples with high SOCS-3 expression. In the ANOVA model, SOCS-3 was confirmed to negatively explain leptin-induced expression of NO, IL-6, MMP-1, MMP-3, iNOS and COX-2 independently of BMI and age (p = 0.008; 0.009; 0.064; 0.008; 0.001; 0.006, respectively). Accordingly, downregulation of SOCS-3 by siRNA in H4 chondrocytes enhanced leptin-induced expression of NO, iNOS, IL-6, MMP-3 and MMP-13.

Conclusion: Previous studies have shown that leptin levels are increased in obesity and leptin has detrimental effects in cartilage. The present results show that SOCS-3 negatively regulates catabolic and proinflammatory effects of leptin in cartilage, suggesting that SOCS-3 could be a future drug target in the treatment or prevention of obesity-induced OA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/suppressor-of-cytokine-signaling-3-negatively-modulates-leptin-mediated-catabolic-and-proinflammatory-effects-in-cartilage-new-potential-mechanism-to-target-obesity-induced-osteoarthritis/