Mitochondrial function is impaired in osteoarthritis (OA) but its impact on cartilage catabolism is not fully understood. Here, we investigated the molecular mechanism of mitochondrial dysfunction-induced activation of the catabolic response in chondrocytes. Using cartilage slices from normal and OA cartilage, we showed that mitochondrial membrane potential was lower in OA cartilage, and that this was associated with increased production of mitochondrial superoxide and catabolic genes [interleukin 6 (IL-6), COX-2 (also known as PTGS2), MMP-3, -9, -13 and ADAMTS5]. Pharmacological induction of mitochondrial dysfunction in chondrocytes and cartilage explants using carbonyl cyanide 3-chlorophenylhydrazone increased mitochondrial superoxide production and the expression of IL-6, COX-2, MMP-3, -9, -13 and ADAMTS5, and cartilage matrix degradation. Mitochondrial dysfunction-induced expression of catabolic genes was dependent on the JNK (herein referring to the JNK family)/activator protein 1 (AP1) pathway but not the NFB pathway. Scavenging of mitochondrial superoxide with MitoTEMPO, or pharmacological inhibition of JNK or cFos and cJun, blocked the mitochondrial dysfunction-induced expression of the catabolic genes in chondrocytes. We demonstrate here that mitochondrial dysfunction contributes to OA pathogenesis via JNK/AP1-mediated expression of catabolic genes. Our data shows that AP1 could be used as a therapeutic target for OA management.

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骨关节炎 (OA) 中线粒体功能受损，但其对软骨分解代谢的影响尚不完全清楚。在这里，我们研究了线粒体功能障碍诱导软骨细胞分解代谢反应激活的分子机制。使用正常软骨和 OA 软骨的软骨切片，我们发现 OA 软骨中的线粒体膜电位较低，这与线粒体超氧化物和分解代谢基因 [白细胞介素 6 (IL-6)、COX-2（也称为如 PTGS2)、MMP-3、-9、-13 和 ADAMTS5]。使用羰基氰化物 3-氯苯腙对软骨细胞和软骨外植体中的线粒体功能障碍进行药理学诱导，增加线粒体超氧化物的产生以及 IL-6、COX-2、MMP-3、-9、-13 和 ADAMTS5 的表达，以及软骨基质降解。线粒体功能障碍诱导的分解代谢基因表达依赖于 JNK（本文指 JNK 家族）/激活蛋白 1 (AP1) 途径，而不是 NFB 途径。用 MitoTEMPO 清除线粒体超氧化物，或对 JNK 或 cFos 和 cJun 进行药理抑制，可阻断线粒体功能障碍诱导的软骨细胞中分解代谢基因的表达。我们在此证明，线粒体功能障碍通过 JNK/AP1 介导的分解代谢基因表达促进 OA 发病机制。我们的数据表明 AP1 可用作 OA 管理的治疗靶点。

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