Zhao X, Dong Y, Zhang J, Li D, Hu G, Yao J, Li Y, Huang P, Zhang M, Zhang J, Huang Z, Zhang Y, Miao Y, Xu Q, Li H
Department of Orthopaedics, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Joint Surgery, The First People's Hospital of Lianyungang, Lianyungang, China.
Cell Death Dis. 2016 Apr 14;7(4):e2188. doi: 10.1038/cddis.2016.68.
Body weight is a component of the mechanical theory of OA (osteoarthritis) pathogenesis. Obesity was also found to be a risk factor for digital OA involving non-weight-bearing joints, which suggested that metabolism influences the occurrence and progression of OA. The metabolic origin of OA has been partially attributed to the involvement of adipokines, such as leptin, the levels of which are significantly and positively correlated with cartilage degeneration in OA patients. However, the mechanisms by which leptin-induced cartilage degeneration occurs are poorly understood. The discovery of chondrogenic progenitor cells (CPCs) opened up new opportunities for investigation. Investigating the effects of leptin on differentiation and proliferation in CPCs would increase our understanding of the roles played by leptin in the aetiology and development of OA. Here, CPCs were harvested using single-cell sorting from rat cartilage tissues to obtain mesenchymal stem-like cells, which possess clonogenicity, proliferation and stemness. High doses of leptin decreased the ability of the CPCs to migrate, inhibited their chondrogenic potential and increased their osteogenic potential, suggesting that leptin changes differentiation fates in CPCs. High doses of leptin induced cell cycle arrest and senescence in CPCs by activating the p53/p21 pathway and inhibiting the Sirt1 pathway. Inhibiting the Sirt1 pathway accelerated cartilage senescence in knockout (KO) mice. Activating the leptin pathway induced higher Ob-Rb expression and was significantly correlated with cartilage degeneration (lower levels of Coll-2) and tissue senescence (higher levels of p53/p21 and lower levels of Sirt1) in OA patients, suggesting that leptin-induced CPCs senescence contributes to the development of OA. Taken together, our results reveal new links between obesity and cartilage damage that are induced by leptin-mediated effects on cell behaviour and senescence.
体重是骨关节炎（OA）发病机制力学理论的一个组成部分。肥胖也被发现是涉及非负重关节的手指OA的一个风险因素，这表明新陈代谢会影响OA的发生和发展。OA的代谢起源部分归因于脂肪因子的参与，如瘦素，其水平与OA患者软骨退变显著正相关。然而，瘦素诱导软骨退变发生的机制尚不清楚。软骨生成祖细胞（CPCs）的发现为研究开辟了新的机会。研究瘦素对CPCs分化和增殖的影响将增进我们对瘦素在OA病因学和发展中所起作用的理解。在此，通过从大鼠软骨组织中进行单细胞分选收获CPCs，以获得具有克隆性、增殖能力和干性的间充质干细胞样细胞。高剂量瘦素降低了CPCs的迁移能力，抑制了它们的软骨生成潜能，并增加了它们的成骨潜能，这表明瘦素改变了CPCs的分化命运。高剂量瘦素通过激活p53/p21途径并抑制Sirt1途径诱导CPCs细胞周期停滞和衰老。抑制Sirt1途径加速了基因敲除（KO）小鼠的软骨衰老。激活瘦素途径诱导更高的Ob-Rb表达，并与OA患者的软骨退变（Coll-2水平降低）和组织衰老（p53/p21水平升高和Sirt1水平降低）显著相关，这表明瘦素诱导的CPCs衰老促进了OA的发展。综上所述，我们的结果揭示了肥胖与瘦素介导的对细胞行为和衰老的影响所诱导的软骨损伤之间的新联系。
