TGF-β/Alk5 signaling prevents osteoarthritis initiation via regulating the senescence of articular cartilage stem cells
TGF-β/Alk5 signaling prevents osteoarthritis initiation via regulating the senescence of articular cartilage stem cells
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TGFββ/Alk5 信号传导通过调节关节软骨干细胞的衰老来预防骨关节炎的发生
DOI：
10.1002/jcp.30231
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发表时间：
2021-01-16
影响因子：
5.6
通讯作者：
Chen, Lin
中科院分区：
文献类型：
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作者：
Tan, Qiaoyan;Wang, Quan;Chen, Lin
骨关节炎（OA）是最常见的关节疾病。在骨性关节炎发病过程中，关节软骨表面是关节软骨（AC）的防御和第一个受影响的结构。Alk5信号传导对于维持AC稳态至关重要，然而，Alk5信号传导参与AC表面关节软骨干细胞（ACSCs）表型的作用和潜在机制尚不清楚。通过ACSCs特异性Alk5缺失（cKO）小鼠模型探讨了Alk5在OA发展中的作用。组织学上评价软骨结构的改变。采用SA - β - gal检测衰老，采用活性氧（ROS）、MitoTracker和LysoTracker染色检测衰老相关的变化。此外，小鼠关节内注射更昔洛韦以限制衰老细胞（SnCs）的有害作用。在衰老和手术诱导的OA条件下，Alk5 cKO小鼠显示慢细胞周期细胞数量减少，表面润滑剂分泌减少，同时软骨退变急剧加速。进一步的研究表明，缺乏Alk5的ACSCs表现出衰老样的表现，包括增殖和分化减少，更多的SA - β - gal阳性细胞和ROS的产生，以及线粒体和溶酶体的明显肿胀。我们进一步发现，局部限制SnCs的有害作用可以减轻创伤后OA的发展。综上所述，我们的研究结果表明，在AC维持和OA启动过程中，Alk5信号在浅层SnCs中起着重要的调节作用。
Osteoarthritis (OA) is the most common joint disease. The surface of joint cartilage is a defensive and first affected structure of articular cartilage (AC) during the pathogenesis of OA. Alk5 signaling is critical for maintaining AC homeostasis, however, the role and underlying mechanism for the involvement of Alk5 signaling in the phenotypes of articular cartilage stem cells (ACSCs) at the surface of AC is still unclear. The role of Alk5 in OA development was explored using an ACSCs‐specific Alk5‐deficient (cKO) mouse model. Alterations in cartilage structure were evaluated histologically. Senescence was detected by SA‐β‐gal, while reactive oxygen species (ROS), MitoTracker, and LysoTracker staining were used to detect changes related to senescence. In addition, mice were injected intra‐articularly with ganciclovir to limit the detrimental roles of senescent cells (SnCs). Alk5 cKO mice showed a decreased number of the slow‐cell cycle cells and less lubricant secretion at the surface accompanied with drastically accelerated cartilage degeneration under ageing and surgically induced OA conditions. Further studies showed that Alk5 deficient ACSCs exhibited senescence‐like manifestations including decreased proliferation and differentiation, more SA‐β‐gal‐positive cells and ROS production, as well as significantly swollen mitochondria and lysosome breakdown. We further found that local limitation of the detrimental roles of SnCs can attenuate the development of posttraumatic OA. Taken together, our findings suggest that Alk5 signaling acts as an important regulator of the SnCs in the superficial layer during AC maintenance and OA initiation.