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Obesity has been associated with osteoarthritis (OA) due to increased mass and metabolic factors which are independent of the biomechanical contribution to joint load. Resveratrol, a natural polyphenolic compound, exerts protective effects on OA through its anti-inflammatory property. However, the mechanism of resveratrol on obesity-related OA is unclear. To investigate the effect and possible mechanism of oral resveratrol on obesity-related OA, we fed C57BL/6J mice with a high-fat diet (HFD) for 16 weeks to establish obesity-related OA model; then two doses (22.5 mg/kg and 45 mg/kg) of resveratrol were given by gavage for additional 12 weeks. Mice with HFD significantly increased body weights compared to the control mice, while resveratrol treatment did not cause obvious weight loss. Histological assessments showed that resveratrol at 45 mg/kg significantly improved OA symptoms. Levels of serum IL-1β and leptin were decreased by resveratrol treatment and positively correlated with Mankin scores. Moreover, resveratrol significantly inhibited the expression of TLR4 and TRAF6 in cartilage. These results suggest that HFD induced obesity can lead to the occurrence of OA, and resveratrol may alleviate OA pathology by decreasing the levels of systematic inflammation and/or inhibiting TLR4 signaling pathway in cartilage. Thus, resveratrol might be a promising therapeutic treatment for obesity-related OA.

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Osteoarthritis (OA) is associated with chronic low-grade inflammation. Resveratrol exerts protective effects on OA through its anti-inflammatory property; however, the mechanism of resveratrol on anti-inflammatory signaling pathways has not been fully elucidated yet. The aim of the present study was to investigate whether resveratrol-mediated PI3K/Akt expression is linked to TLR4/NF-κB pathway and the role of TLR4/Akt/FoxO1 axis in the anti-osteoarthritic effect of resveratrol. Methods: SW1353 cells stimulated by IL-1β (10 ng/mL) were cultured in the presence or absence of resveratrol (50 μM) and then treated with TLR4 siRNA, PI3K inhibitor LY294002 or FoxO1 siRNA, respectively. The associated proteins of TLR4 signaling pathways and TLR4/Akt/FoxO1 axis were evaluated by Western blot. The level of IL-6 in the supernatant was detected by ELISA. Results: IL-1β treatment increased the expression of TLR4/NF-κB and phosphorylation of PI3K/Akt and FoxO1, while additional resveratrol further upregulated the expression of PI3K/Akt and FoxO1 phosphorylation but downregulated TLR4 signals in SW1353 cells. Further analyses by the inhibition of TLR4, PI3K/Akt and FoxO1 signaling pathways, respectively, showed that the activation of TLR4 can induce PI3K/Akt phosphorylation, which increases the phosphorylation of FoxO1 and inactivates it. Next, inactivated-FoxO1 can reduce the expression of TLR4, which forms a self-limiting mechanism of inflammation. Resveratrol treatment can upregulate PI3K/Akt phosphorylation and inactivate FoxO1, thereby reducing TLR4 and inflammation. Conclusion: This study reveals that TLR4/Akt/FoxO1 inflammatory self-limiting mechanism may exist in IL-1β-stimulated SW1353 cells. This study reveals a novel cross-talk mechanism which is between integrated PI3K/Akt/FoxO1 signaling network and TLR4driven innate responses in IL-1β-stimulated SW1353 cells. Resveratrol may exert anti-OA effect by enhancing the self-limiting mechanism of inflammation through TLR4/Akt/FoxO1 axis.

Obesity is considered as a risk factor of osteoarthritis (OA), but the precise relationship is still poorly understood. Leptin, one of the most relevant factors secreted by adipose tissues, plays an important role in the pathogenesis of OA. Our aim was to investigate the regulation and molecular mechanism of the leptin signaling pathway in obesity-related OA. SD rats were fed with a high-fat diet (HFD) for 5, 15, and 27 weeks. The levels of leptin in serum increased from W5, while in the synovial fluid increased from W15. The histological evaluation showed that the pathological changes of OA occurred at 27 weeks rather than 5 or 15 weeks. We also found that leptin induced CD14/TLR4 activation by the JAK2-STAT3 signaling pathway to promote OA. Moreover, silencing SOCS3 enhanced leptin-induced JAK2-STAT3-CD14/TLR4 activation in rat primary chondrocytes. Our findings indicated that leptin may be one of the initiating factors of obesity-related OA. TLR4 is at least partially regulated by leptin through the JAK2-STAT3-CD14 pathway. Meanwhile, SOCS3 acting as a negative feedback inhibitor of leptin signaling presented a potential therapeutic prospect for obesity-related OA. Our study provided new evidence suggesting the key role of leptin in mediating obesity-related OA process and its underlying mechanisms.