Department of Rehabilitation Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, PR China.
Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, Liaoning Province, PR China.
Int Immunopharmacol. 2023 Dec;125(Pt B):111191. doi: 10.1016/j.intimp.2023.111191. Epub 2023 Nov 9.
Osteoarthritis (OA) is a chronic joint disease characterized by the progressive degradation of articular cartilage. In this study, as determined by histological staining, the cartilage surface of the OA rats was damaged, defective and broken, and chondrocytes and proteoglycan were reduced. While moderate physical exercise showed protective effects on the cartilage. Besides, RNA-seq was performed to select a target protein and RNF125 (an E3 ubiquitin ligase) was decreased in the cartilage tissues of OA rats and increased after physiological exercise. However, the precise role of RNF125 in OA is still unknown. This work aimed to investigate the involvement and underlying mechanism of RNF125 in OA pathogenesis. Our results defined that adenovirus-mediated overexpression of RNF125 inhibited the degradation of extracellular matrix of chondrocytes induced by IL-1β, as revealed by increased chondrocyte viability, upregulated COL2A1 and ACAN levels, and downregulated MMP1, MMP13 and ADAMTS5 levels, which was abrogated by NR4A2 knockdown. In vivo, RNF125 relieved OA, manifested as reduced cartilage injury and increased chondrocytes. Mechanically, NFATC2 bound to the RNF125 promoter and directly regulated RNF125 transcription, as illustrated by luciferase reporter, Ch-IP and DNA pull-down assays. Furthermore, RNF125 overexpression inhibited the nuclear translocation of β-catenin, thus suppressing activation of the Wnt/β-catenin signaling pathway. Also, RNF125 as E3 ubiquitin ligase led to the ubiquitination and degradation of TRIM14 protein, and TRIM14 overexpression efficiently reversed the effects of RNF125 overexpression on OA progression. Totally, this study provides new insights into OA pathogenesis regulated by RNF125. RNF125 may be a novel biomarker for OA therapy.
骨关节炎（OA）是一种慢性关节疾病，其特征是关节软骨进行性退化。在这项研究中，通过组织学染色发现，OA 大鼠的软骨表面受损、有缺陷和破裂，软骨细胞和蛋白聚糖减少。而适度的体育锻炼对软骨有保护作用。此外，进行了 RNA-seq 以选择靶蛋白，结果发现 RNF125（一种 E3 泛素连接酶）在 OA 大鼠的软骨组织中减少，而在生理运动后增加。然而，RNF125 在 OA 中的精确作用仍不清楚。这项工作旨在研究 RNF125 参与 OA 发病机制及其潜在机制。我们的研究结果表明，腺病毒介导的 RNF125 过表达抑制了 IL-1β诱导的软骨细胞细胞外基质的降解，这表现在增加了软骨细胞的活力、上调了 COL2A1 和 ACAN 的水平，以及下调了 MMP1、MMP13 和 ADAMTS5 的水平，而 NR4A2 敲低则消除了这种作用。在体内，RNF125 缓解了 OA，表现为软骨损伤减少和软骨细胞增加。在机制上，NFATC2 与 RNF125 启动子结合，并直接调节 RNF125 转录，如荧光素酶报告基因、Ch-IP 和 DNA 下拉实验所示。此外，RNF125 过表达抑制了 β-catenin 的核易位，从而抑制了 Wnt/β-catenin 信号通路的激活。此外，RNF125 作为 E3 泛素连接酶导致 TRIM14 蛋白的泛素化和降解，而 TRIM14 过表达有效地逆转了 RNF125 过表达对 OA 进展的影响。总的来说，这项研究为 RNF125 调节的 OA 发病机制提供了新的见解。RNF125 可能是 OA 治疗的一种新的生物标志物。
