Yang Zhijian, Zeng Anyu, Yu Baoxi, Xie Chao, Zhu Weiwen, Liu Hailong, Gu Cheng, Fu Ming
Department of Joint Surgery, First Affiliated Hospital of Sun Yat-Sen University, Zhongshan Second Road 58 Th, Guangzhou, Guangdong, China.
Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
Biochem Genet. 2025 May 28. doi: 10.1007/s10528-025-11143-x.
Osteoarthritis (OA), characterized by progressive cartilage degradation, is a leading cause of chronic disability in older adults. Although the molecular mechanisms underlying OA remain incompletely understood, emerging evidence suggests that long non-coding RNAs (lncRNAs) play critical regulatory roles. Recently, we identified a previously uncharacterized lncRNA, RP13-516M14.1, that regulates autophagy in OA chondrocytes. In this study, we aimed to elucidate the mechanism of RP13-516M14.1 in OA pathogenesis. The expression of RP13-516M14.1 was assessed in OA cartilage samples. Its biological functions were investigated using RNA sequencing, RT-qPCR, western blotting, LC3 puncta imaging, transmission electron microscopy (TEM), and atomic force microscopy (AFM) nanoindentation. Its interactions with miR-429 were verified by RNA pull-down assays, RNA immunoprecipitation, fluorescence in situ hybridization (FISH), and dual-luciferase reporter assays. RP13-516M14.1 was identified as key regulator of autophagy, maintaining cartilage homeostasis through modulation of miR-429. Knockdown of RP13-516M14.1 exacerbated OA phenotypes both in vitro and in vivo, while its overexpression protected cartilage by promoting autophagy via miR-429/DDIT4 axis. Notebly, RP13-516M14.1 functioned both as a competitive endogenous RNA (ceRNA) sponging miR-429 and directly regulating its expression. Our study highlights the critical role of RP13-516M14.1 in regulating autophagy in chondrocytes and suggests its potential as a therapeutic target for OA treatment.
骨关节炎（OA）以进行性软骨退变 为特征，是老年人慢性残疾的主要原因。尽管OA的分子机制仍未完全明确，但新出现的证据表明长链非编码RNA（lncRNA）发挥着关键的调节作用。最近，我们鉴定出一种以前未被描述的lncRNA，即RP13-516M14.1，它可调节OA软骨细胞中的自噬。在本研究中，我们旨在阐明RP13-516M14.1在OA发病机制中的作用机制。在OA软骨样本中评估了RP13-516M14.1的表达。使用RNA测序、RT-qPCR、蛋白质免疫印迹、LC3斑点成像、透射电子显微镜（TEM）和原子力显微镜（AFM）纳米压痕技术研究了其生物学功能。通过RNA下拉试验、RNA免疫沉淀、荧光原位杂交（FISH）和双荧光素酶报告基因试验验证了它与miR-429的相互作用。RP13-516M14.1被确定为自噬的关键调节因子，通过调节miR-429维持软骨内环境稳定。敲低RP13-516M14.1在体外和体内均加剧了OA表型，而其过表达则通过miR-429/DDIT4轴促进自噬来保护软骨。值得注意的是，RP13-516M14.1既作为竞争性内源RNA（ceRNA）海绵吸附miR-429，又直接调节其表达。我们的研究突出了RP13-516M14.1在调节软骨细胞自噬中的关键作用，并表明其作为OA治疗靶点的潜力。
