n-3 polyunsaturated fatty acids alleviate the progression of obesity-related osteoarthritis and protect cartilage through inhibiting the HMGB1-RAGE/TLR4 signaling pathway.

Osteoarthritis (OA) is a common joint degenerative disease. There is currently no cure for OA. Dietary fatty acids have potential value in the prevention and treatment of OA. n-3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory effects, but their anti-OA mechanism remains unclear. High-mobility group box 1 (HMGB1) promotes inflammation and participates the pathogenesis of OA. The purpose of this study was to investigate the protective effect of n-3 PUFAs on cartilage and whether n-3 PUFAs could exert an anti-OA effect through inhibiting HMGB1-RAGE/TLR4 signaling pathway. We established an obesity-related post-traumatic OA mice model and an in vitro study was conducted to explore the regulatory mechanism of n-3 PUFAs on HMGB1 and its signal pathway against OA. We found that diet rich in n-3 PUFAs alleviated OA-like lesions of articular cartilage with the decrease of HMGB1-RAGE/TLR4 signaling protein in mice. In SW1353 cells, DHA significantly reduced the expression of HMGB1-RAGE/TLR4 signaling protein which was up-regulated by IL-1ß stimulation. HMGB1 overexpression reversed the inhibitory effect of DHA on HMGB1-RAGE/TLR4 signaling pathway. The activation of SIRT1 may participate the inhibitory effect of DHA on HMGB1-RAGE/TLR4 signaling pathway. In conclusion, n-3 PUFAs could attenuate the progression of obesity-related OA and exert protective effect on cartilage by inhibiting HMGB1-RAGE/TLR4 signaling pathway, which may be associated with the activation of SIRT1. Dietary n-3 PUFAs supplements can be considered as a potential therapeutic substance for OA.

Dietary Fatty Acid Regulation of the NLRP3 Inflammasome via the TLR4/NF-κB Signaling Pathway Affects Chondrocyte Pyroptosis.

Dietary fatty acid (FA) content and type have different effects on obesity-associated osteoarthritis (OA), but the mechanisms underlying these differences are not fully understood. Inflammation activated by toll-like receptor 4 (TLR4)/nuclear factor- (NF-) κB signaling and pyroptosis induced by the NLRP3/caspase-1/gasdermin D (GSDMD) signaling pathway play important roles in OA development. Our aim in this study was to observe the effects of dietary FAs on the articular cartilage of obese post-traumatic OA model mice and on chondrocytes stimulated by lipopolysaccharide (LPS) and to determine whether the underlying mechanisms involve TLR4/NF-κB and NLRP3/caspase-1/GSDMD signaling pathways. Mice were fed high-fat diets rich in various FAs and underwent surgical destabilization of the medial meniscus to establish the obesity-related post-traumatic OA model. LPS-induced SW1353 chondrosarcoma cells were used to mimic OA status in vitro, and TLR4 inhibitors or TLR4 overexpressing lentivirus was administered. Analysis using weight-matched mice and multiple regression models revealed that OA was associated with dietary FA content and serum inflammatory factor levels, but not body weight. Diets rich in n-3 polyunsaturated fatty acids (PUFAs) attenuated OA and inhibited the TLR4/NF-κB and NLRP3/caspase-1/GSDMD signaling pathways, whereas diets rich in saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), or n-6 PUFAs increased OA severity and activated these pathways. In vitro results for SFAs, n-6 PUFAs, and n-3 PUFAs were consistent with the animal experiments. However, those for MUFAs were not. FA effects on the NLRP3/caspase-1/GSDMD pathway were associated with the inhibition or activation of the TLR4 signaling pathway. In conclusion, diets rich in SFAs or n-6 PUFAs can exacerbate obesity-associated OA, whereas those rich in n-3 PUFAs have protective effects against this disease, due to their respective pro-/anti-inflammatory and pyroptotic effects. Further research on dietary FA supplements as a potential therapeutic approach for OA is needed.