Mechanical overloading promotes chondrocyte senescence and osteoarthritis development through downregulating FBXW7
Mechanical overloading promotes chondrocyte senescence and osteoarthritis development through downregulating FBXW7
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DOI：
10.1136/annrheumdis-2021-221513
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发表时间：
2022-01
影响因子：
27.4
通讯作者：
Haiyan Zhang;Yan Shao;Zihao Yao;Liangliang Liu;Hongbo Zhang;J. Yin;Haoyu Xie;Kai Li;
中科院分区：
文献类型：
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作者：
Haiyan Zhang;Yan Shao;Zihao Yao;Liangliang Liu;Hongbo Zhang;J. Yin;Haoyu Xie;Kai Li;
目的探讨机械应力在软骨老化中的作用，并确定骨关节炎（OA）进展过程中的机械关联。方法观察F-box和WD repeat domain containing 7（FBXW 7）泛素连接酶在体外培养、实验性OA小鼠和人OA软骨中的表达及软骨细胞衰老。产生在软骨细胞中具有Fbxw 7敲除的小鼠，并将表达Fbxw 7的腺病毒（AAV-Fbxw 7）关节内注射到小鼠中。进行内侧半月板失稳手术以诱导OA。使用骨关节炎研究学会国际评分测量软骨损伤，并确定软骨细胞衰老的变化。在来自Fbxw 7敲除小鼠和对照小鼠的关节软骨中进行mRNA测序。结果机械负荷加速了体外培养软骨细胞和小鼠关节软骨的衰老。FBXW 7在原代软骨细胞和小鼠软骨中被机械超载下调，在OA患者、老年小鼠和OA小鼠软骨中下调。软骨细胞中FBXW 7的缺失诱导软骨细胞衰老并加速小鼠的软骨退化，表现为p16 INK 4A、p21和Colx的上调以及Col 2a 1和ACAN的下调，这导致OA的恶化。相比之下，关节内注射表达Fbxw 7的腺病毒减轻了小鼠的OA。机械超载降低了Fbxw 7 mRNA转录和FBXW 7介导的MKK 7降解，从而刺激JNK信号传导。特别是，抑制JNK活性的DTP 3，MKK 7抑制剂，改善软骨细胞衰老和软骨变性结论FBXW 7是一个关键因素之间的联系机械超载和软骨细胞衰老和软骨老化的病理OA。
Objectives To investigate the role of mechanical stress in cartilage ageing and identify the mechanistic association during osteoarthritis (OA) progression. Methods F-box and WD repeat domain containing 7 (FBXW7) ubiquitin ligase expression and chondrocyte senescence were examined in vitro, in experimental OA mice and in human OA cartilage. Mice with Fbxw7 knockout in chondrocytes were generated and adenovirus-expressing Fbxw7 (AAV-Fbxw7) was injected intra-articularly in mice. Destabilised medial meniscus surgery was performed to induce OA. Cartilage damage was measured using the Osteoarthritis Research Society International score and the changes in chondrocyte senescence were determined. mRNA sequencing was performed in articular cartilage from Fbxw7 knockout and control mice. Results Mechanical overloading accelerated senescence in cultured chondrocytes and in mice articular cartilage. FBXW7 was downregulated by mechanical overloading in primary chondrocytes and mice cartilage, and decreased in the cartilage of patients with OA, aged mice and OA mice. FBXW7 deletion in chondrocytes induced chondrocyte senescence and accelerated cartilage catabolism in mice, as manifested by an upregulation of p16INK4A, p21 and Colx and downregulation of Col2a1 and ACAN, which resulted in the exacerbation of OA. By contrast, intra-articular injection of adenovirus expressing Fbxw7 alleviated OA in mice. Mechanistically, mechanical overloading decreased Fbxw7 mRNA transcription and FBXW7-mediated MKK7 degradation, which consequently stimulated JNK signalling. In particular, inhibition of JNK activity by DTP3, a MKK7 inhibitor, ameliorated chondrocyte senescence and cartilage degeneration Conclusions FBXW7 is a key factor in the association between mechanical overloading and chondrocyte senescence and cartilage ageing in the pathology of OA.