Sirt1 involved in cellular aging and aging-related diseases, including osteoarthritis (OA). Our previous study showed Sirt1 played a role in the pathogenesis of OA, however, the underlying mechanisms are still poorly elicited. In this study, we investigated the role of Sirt1 in epigenetically regulating P53/P21 pathway in a Sirt1 loss model. Sirt1 deletion male mice (n = 10) with destabilization of the medial meniscus (DMM) were used to observe its role on OA development. Then, the relationships between SIRT1 and P53 were detected by Coimmunoprecipitation (CoIP), and the gain-off function of P53 gene was indicated by P53 activators and inhibitors in vitro. Finally, human cartilage samples from patients with OA were collected. Sirt1 deletion mice displayed a spontaneous OA development, manifesting severe chondrocytes hypertrophy markers MMP13 and ADAMTS5, highly expressed P53 and P21. Strikingly, surgery-induced meniscus injury promoted the OA pathogenesis and apoptosis in Sirt1 deficient mice. Ultimately, our CoIP data demonstrated that Sirt1 directly interacted with P53 in vitro. However inhibition of P53 alleviated OA progression. We also observed that chondrocyte apoptosis and P53 increased in osteoarthritis (OA) progression with a declining expression of Sirt1 in human cartilage. Loss of Sirt1 in cartilage led to accelerated OA pathogenesis via aberrant activation of p53/p21 mediated senescence associated secretory phenotype, hypertrophy and apoptosis.

Sirt1参与细胞衰老和与衰老相关的疾病，包括骨关节炎（OA）。我们以前的研究表明Sirt1在OA的发病机理中起作用，但是，其潜在机制仍然很少。在这项研究中，我们调查了Sirt1在Sirt1缺失模型中表观遗传调控P53 / P21途径中的作用。内侧半月板（DMM）不稳定的Sirt1缺失雄性小鼠（n = 10）用于观察其对OA发育的作用。然后，通过共免疫沉淀法（CoIP）检测SIRT1和P53之间的关系，并通过P53激活剂和抑制剂指示P53基因的增益功能。最后，从OA患者中收集人软骨样品。Sirt1缺失小鼠表现出自发的OA发育，表现出严重的软骨细胞肥大标记MMP13和ADAMTS5，高表达P53和P21。引人注目的是，手术诱发的半月板损伤促进了Sirt1缺陷小鼠的OA发病机理和细胞凋亡。最终，我们的CoIP数据表明Sirt1在体外与P53直接相互作用。然而，P53的抑制减轻了OA的进展。我们还观察到软骨细胞凋亡和P53在骨关节炎（OA）进展中增加，而Sirt1在人软骨中的表达下降。Sirt1的损失 通过异常激活p53 / p21介导的衰老相关的分泌表型，肥大和凋亡，软骨中的α-淀粉样蛋白导致OA发病机理加速。