Different n-6/n-3 PUFA diets with fish oil attenuated osteoarthritis in ovariectomized mice via targeting the NLRP3 inflammasome

Abstract Osteoporosis(OP) and osteoarthritis(OA) co-exist with increased inflammatory cytokines as a common feature. Modern diet containing high n-6/n-3 PUFA was suggested contributing to these chronic inflammatory diseases. Although fish oil (FO) rich in n-3 PUFAs has been confirmed beneficial for OA and bone loss in previous studies, whether small amounts of FO could alleviate osteoporotic OA under a high n-6/n-3 PUFA condition has not been reported. In this study, the osteoporotic OA mice were fed with 20:1 or 6:1 n-6/n-3 PUFA diets with or without FO for 12 weeks. The results showed that 20:1 diet with FO ameliorated systemic inflammation and cartilage degradation in model mice, compared to the non-FO 20:1 diet. Specifically, diets with FO altered the fatty acids composition with elevating n-3/n-6 PUFA in articular cartilage, thus restoring the cartilage homeostasis by inhibiting the catabolic process. Mechanistically, 20:1 non-FO diet promoted the expression of NLRP3 via PGE2/EP4/NFκB. However, 20:1 FO-H diet significantly inhibited the expression of NLRP3 and further exhibited a greater affinity for GPR120 than 20:1 non-FO diet to inactivate caspase-1-dependent NLRP3 inflammasome. As a consequence, 20:1 FO-H diet inhibited chondrocyte pyroptosis and followed by the reduction of the two catabolic cytokines: IL-1β and IL-18. Notably, the 20:1 FO-H diet performed as well as the 6:1 non-FO diet, and 6:1 diet with FO could further improve osteoporotic OA in a dose-dependent manner. This study demonstrated that FO could attenuate the adverse effect of 20:1 n-6/n-3 PUFA diet on osteoporotic OA, providing skeletal evidence for healthy diet.