Si Hai-Bo, Yang Ti-Min, Li Lan, Tian Mei, Zhou Li, Li Dai-Ping, Huang Qiang, Kang Peng-de, Yang Jing, Zhou Zong-Ke, Cheng Jing-Qiu, Shen Bin
Department of Orthopaedics and National Clinical Research Centre for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China.
Department of Orthopaedics and National Clinical Research Centre for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China; Department of Orthopaedics, Tibet Autonomous Region People's Hospital, Lasa 850000, China.
Mol Ther Nucleic Acids. 2020 Mar 6;19:15-30. doi: 10.1016/j.omtn.2019.10.032. Epub 2019 Nov 9.
Osteoarthritis (OA) is a major cause of joint pain and disability, and chondrocyte senescence is a key pathological process in OA and may be a target of new therapeutics. MicroRNA-140 (miR-140) plays a protective role in OA, but little is known about its epigenetic effect on chondrocyte senescence. In this study, we first validated the features of chondrocyte senescence characterized by increased cell cycle arrest in the G0/G1 phase and the expression of senescence-associated β-galactosidase (SA-βGal), p16, p21, p53, and γH2AX in human knee OA. Then, we revealed in interleukin 1β (IL-1β)-induced OA chondrocytes in vitro that pretransfection with miR-140 effectively inhibited the expression of SA-βGal, p16, p21, p53, and γH2AX. Furthermore, in vivo results from trauma-induced early-stage OA rats showed that intra-articularly injected miR-140 could rapidly reach the chondrocyte cytoplasm and induce molecular changes similar to the in vitro results, resulting in a noticeable alleviation of OA progression. Finally, bioinformatics analysis predicted the potential targets of miR-140 and a mechanistic network by which miR-140 regulates chondrocyte senescence. Collectively, miR-140 can effectively attenuate the progression of early-stage OA by retarding chondrocyte senescence, contributing new evidence of the involvement of miR-mediated epigenetic regulation of chondrocyte senescence in OA pathogenesis.
骨关节炎（OA）是关节疼痛和残疾的主要原因，软骨细胞衰老在OA中是关键的病理过程，可能是新疗法的靶点。微小RNA-140（miR-140）在OA中发挥保护作用，但对其对软骨细胞衰老的表观遗传效应知之甚少。在本研究中，我们首先验证了人膝关节OA中软骨细胞衰老的特征，其表现为细胞周期在G0/G1期停滞增加以及衰老相关β-半乳糖苷酶（SA-βGal）、p16、p21、p53和γH2AX的表达。然后，我们发现在体外白细胞介素1β（IL-1β）诱导的OA软骨细胞中，预先转染miR-140可有效抑制SA-βGal、p16、p21、p53和γH2AX的表达。此外，创伤诱导的早期OA大鼠的体内结果表明，关节内注射miR-140可迅速到达软骨细胞胞质，并诱导与体外结果相似的分子变化，从而显著减轻OA进展。最后，生物信息学分析预测了miR-140的潜在靶点以及miR-140调节软骨细胞衰老的机制网络。总的来说，miR-140可通过延缓软骨细胞衰老有效减轻早期OA的进展，为miR介导的软骨细胞衰老表观遗传调控参与OA发病机制提供了新证据。
