Mitochondrial dysfunction exacerbates inflammatory responses via the JNK/p38-AP-1 pathway in primary cultured chondrocytes

Although mitochondrial dysfunction associated with aging and stress may be involved in chondrocyte abnormalities, its role in chondrocyte inflammatory responses remains largely unknown. In this study, we investigated the effects of rotenone, which triggers mitochondrial dysfunction, on the inflammatory responses induced by interleukin-1β (IL-1β) in primary cultured rat chondrocytes. Co-treatment with rotenone and IL-1β significantly increased the expression of matrix metalloproteinase 3, interleukin-6, and tumor necrosis factor, which are associated with osteoarthritis (OA) pathology, compared with treatment with each agent alone. The co-treatment with rotenone and IL-1β also increased the phosphorylation of c-Jun N-terminal kinase (JNK), p38, and c-Jun compared with treatment with each agent alone. Meanwhile, treatment with inhibitors of JNK, p38, and activator protein-1 (AP-1) prevented the potentiating effects of the co-treatment with rotenone and IL-1β on the gene expression of inflammatory factors. Regarding the shift from oxidative phosphorylation to glycolysis in response to rotenone, hexokinase was involved in the potentiated inflammatory factor expression and phosphorylation of JNK and p38 induced by the co-treatment with rotenone and IL-1β. These results suggest that rotenone-induced mitochondrial dysfunction enhances the IL-1β-induced inflammatory responses by increasing the activity of the JNK/p38-AP-1 signaling pathway in cultured chondrocytes. Taken together, the present findings suggest a possible mechanism for the exacerbated inflammatory responses observed in OA pathology, and may contribute to the available drug targets for the development of therapeutic agents for OA.