Jiang Huanyu, Zhang Yubiao, Hu Geliang, Ji Piyao, Ming Jianghua, Li Yaming, Zhou Yan
Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China.
Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China.
Commun Biol. 2024 Dec 24;7(1):1695. doi: 10.1038/s42003-024-07407-8.
Osteoarthritis (OA) is a common age-related disease that is correlated with a high number of senescent chondrocytes in joint tissues. Heterogeneous nuclear ribonucleoprotein D (HNRNPD) is an RNA-binding protein whose expression imbalance is associated with cell senescence, but the role of HNRNPD in the occurrence and development of OA has not been reported. In this study, HNRNPD was found to be associated with the chondrocyte senescence process. We determined the factors at the posttranscriptional level that regulated the expression of the genes that induce OA and found that HNRNPD was specifically highly expressed in OA-induced rat cartilage and in human OA cartilage. Recombinant adeno-associated virus (rAAV)-mediated HNRNPD gene overexpression alone did not significantly regulate the occurrence and development of OA in the physiological state of the joint. However, rAAV-HNRNPD significantly exacerbated experimental OA in rats subjected to destabilization of the medial meniscus. Overexpression of HNRNPD promoted mitochondrial dysfunction and the expression of FOXM1, which acts as a direct target. Furthermore, downregulation of FOXM1 in chondrocytes weakened the HNRNPD-mediated promotion of chondrocyte senescence and mitochondrial dysfunction. Our results suggest that the RNA-binding protein HNRNPD promotes chondrocyte senescence in the pathology of OA by upregulating FOXM1.
骨关节炎（OA）是一种常见的与年龄相关的疾病，与关节组织中大量衰老的软骨细胞相关。异质性细胞核核糖核蛋白D（HNRNPD）是一种RNA结合蛋白，其表达失衡与细胞衰老有关，但HNRNPD在OA发生发展中的作用尚未见报道。在本研究中，发现HNRNPD与软骨细胞衰老过程相关。我们在转录后水平确定了调节诱导OA的基因表达的因素，发现HNRNPD在OA诱导的大鼠软骨和人类OA软骨中特异性高表达。单独的重组腺相关病毒（rAAV）介导的HNRNPD基因过表达在关节生理状态下并未显著调节OA的发生发展。然而，rAAV-HNRNPD显著加重了内侧半月板失稳大鼠的实验性OA。HNRNPD的过表达促进了线粒体功能障碍以及作为直接靶点的FOXM1的表达。此外，软骨细胞中FOXM1的下调减弱了HNRNPD介导的软骨细胞衰老促进作用和线粒体功能障碍。我们的结果表明，RNA结合蛋白HNRNPD通过上调FOXM1在OA病理过程中促进软骨细胞衰老。
