TGF‐β/Alk5 signaling prevents osteoarthritis initiation via regulating the senescence of articular cartilage stem cells

• Published in: Journal of cellular physiology 2021-07, Vol.236 (7), p.5278-5292
• Main Authors: Tan, Qiaoyan, Wang, Quan, Kuang, Liang, Zhang, Jinfan, Peng, Xiuqin, Liang, Sen, Liu, Mi, Chen, Hangang, Chen, Shuai, Luo, Xiaoqing, Qi, Huabing, Li, Can, Luo, Fengtao, Huang, Shuo, Ni, Zhenhong, Jin, Min, Su, Nan, Yang, Jing, Yang, Peng, Chen, Bo, Chen, Liang, Du, Xiaolan, Xie, Yangli, Chen, Lin
• Format: Article
• Language: English
• Subjects: Aging; Aging (artificial); Alk5; Arthritis; articular cartilage stem cells; Biomedical materials; Cartilage; Cartilage (articular); Cartilage diseases; Cell cycle; Cell proliferation; Degeneration; Ganciclovir; Homeostasis; Joint diseases; Mitochondria; Osteoarthritis; Pathogenesis; Phenotypes; Reactive oxygen species; Senescence; Signaling; Stem cell transplantation; Stem cells
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.30231

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. ACSCs‐specific Alk5‐deficient (cKO) mice showed drastically accelerated cartilage degeneration. Alk5 deficient ACSCs exhibited senescence‐like manifestations. Local limitation of the detrimental roles of senescent cells can attenuate the development of posttraumatic osteoarthritis (OA) in Alk5 cKO mice.