Mitochondrial dysfunction activates cyclooxygenase 2 expression in cultured normal human chondrocytes

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Abstract
Objective Mitochondrial alterations play a key role in the pathogenesis of osteoarthritis (OA). This study evaluated a potential role of mitochondrial respiratory chain (MRC) dysfunction in the inflammatory response of normal human chondrocytes. Methods Commonly used inhibitors of the MRC were utilized to induce mitochondrial dysfunction in normal human chondrocytes. Levels of prostaglandin E2 (PGE2) protein and expression of cyclooxygenase 2 (COX‐2) and COX‐1 messenger RNA (mRNA) and protein were analyzed. To identify the underlying mechanisms responsible for PGE2 liberation, reactive oxygen species (ROS) were measured. Inhibitors of ROS, including vitamin E, and inhibitors of mitochondrial Ca2+ and NF‐κB were used to test their effects on the MRC. Results Antimycin A and oligomycin (inhibitors of mitochondrial complexes III and V, respectively) significantly increased the levels of PGE2 (mean ± SEM 505 ± 132 pg/50,000 cells and 288 ± 104 pg/50,000 cells, respectively, at 24 hours versus a basal level of 29 ± 9 pg/50,000 cells; P < 0.05) and increased the expression of COX‐2 at both the mRNA and protein levels. Expression of COX‐1 did not show any modulation with either inhibitor. Further experiments revealed that antimycin A and oligomycin induced a marked increase in the levels of ROS. Production of PGE2 and expression of COX‐2 protein were inhibited by antioxidants, vitamin E, and mitochondrial Ca2+ and NF‐κB inhibitors. The response to blockers of mitochondrial Ca2+ movement showed that ROS production was dependent on mitochondrial Ca2+ accumulation. Conclusion These results strongly suggest that, in human chondrocytes, the inhibition of complexes III and V of the MRC induces an inflammatory response, which could be especially relevant in relation to PGE2 production via mitochondrial Ca2+ exchange, ROS production, and NF‐κB activation. These data may prove valuable for a better understanding of the participation of mitochondria in the pathogenesis of OA.

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