Kindlin-2 preserves integrity of the articular cartilage to protect against osteoarthritis
Kindlin-2 preserves integrity of the articular cartilage to protect against osteoarthritis
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DOI：
10.1038/s43587-021-00165-w
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发表时间：
2022-04-01
期刊：
影响因子：
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通讯作者：
Xiao, Guozhi
中科院分区：
文献类型：
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作者：
Wu, Xiaohao;Lai, Yumei;Xiao, Guozhi
骨关节炎（OA）是一种与年龄相关的退行性关节疾病，其发病机制尚不清楚。在这里，我们报告Kindlin-2在关节软骨细胞中高度表达，并在老年小鼠和OA患者的退行性软骨中下调。关节软骨细胞中Kindlin-2缺失导致自发性OA并加剧成年小鼠中不稳定诱导的OA病变Kindlin-2缺陷促进线粒体氧化应激并激活Stat 3，导致Runx 2介导的软骨细胞catalysis。药理学抑制Stat 3激活或基因消融Stat 3在软骨细胞逆转Runx 2和细胞外基质降解酶的异常积累，并限制由kindlin-2缺乏引起的OA恶化。在软骨细胞中删除Runx 2逆转了由kindlin-2删除引起的结构变化和OA病变，而不下调p-Stat 3。关节内注射AAV 5-kindlin-2减缓小鼠中老化和不稳定诱导的膝关节OA的进展总的来说，我们确定了关节软骨细胞中由kindlin-2，Stat 3和Runx 2组成的通路，该通路负责维持关节软骨的完整性，并确定了OA的潜在治疗靶点。
Osteoarthritis (OA) is an aging-related degenerative joint disease with a poorly defined mechanism. Here we report that kindlin-2 is highly expressed in articular chondrocytes and downregulated in the degenerated cartilage of aged mice and patients with OA. Kindlin-2 deletion in articular chondrocytes leads to spontaneous OA and exacerbates instability-induced OA lesions in adult mice. Kindlin-2 deficiency promotes mitochondrial oxidative stress and activates Stat3, leading to Runx2-mediated chondrocyte catabolism. Pharmacological inhibition of Stat3 activation or genetic ablation of Stat3 in chondrocytes reverses aberrant accumulation of Runx2 and extracellular-matrix-degrading enzymes and limits OA deteriorations caused by kindlin-2 deficiency. Deleting Runx2 in chondrocytes reverses structural changes and OA lesions caused by kindlin-2 deletion without downregulating p-Stat3. Intra-articular injection of AAV5-kindlin-2 decelerates progression of aging- and instability-induced knee joint OA in mice. Collectively, we identify a pathway consisting of kindlin-2, Stat3 and Runx2 in articular chondrocytes that is responsible for maintaining articular cartilage integrity and define a potential therapeutic target for OA.