Due to the unclear pathogenesis of osteoarthritis (OA), effective treatment for this ailment is presently unavailable. Accumulating evidence points to chondrocyte senescence as a key driver in OA development. This study aims to identify OA-specific microRNAs (miRNAs) targeting chondrocyte senescence to alleviate OA progression. We screened and identified miRNAs differentially expressed in OA and normal cartilage, then confirmed the impact of miR-653-5p on chondrocyte functions and senescence phenotypes through in vitro experiments with overexpression/silencing. We identified interleukin 6 (IL-6) as the target gene of miR-653-5p and confirmed the regulatory influence of miR-653-5p on the IL-6/JAK/STAT3 signaling pathway through gain/loss-of-function studies. Finally, we assessed the therapeutic efficacy of miR-653-5p on OA using a mouse model with destabilization of the medial meniscus. MiR-653-5p was significantly downregulated in cartilage tissues and chondrocytes from OA patients. Overexpression of miR-653-5p promoted chondrocyte matrix synthesis and proliferation while inhibiting chondrocyte senescence. Furthermore, bioinformatics target prediction and the luciferase reporter assays identified IL-6 as a target of miR-653-5p. Western blot assays demonstrated that miR-653-5p overexpression inhibited the protein expression of IL-6, the phosphorylation of JAK1 and STAT3, and the expression of chondrocyte senescence phenotypes by regulating the IL-6/JAK/STAT3 signaling pathway. More importantly, the cartilage destruction was significantly alleviated and chondrocyte senescence phenotypes were remarkably decreased in the OA mouse model treated by agomiR-653-5p compared to the control mice. MiR-653-5p showed a significant decrease in cartilage tissues of individuals with OA, leading to an upregulation of chondrocyte senescence phenotypes in the articular cartilage. AgomiR-653-5p emerges as a potential treatment approach for OA. These findings provide further insight into the role of miR-653-5p in chondrocyte senescence and the pathogenesis of OA.

中文翻译：

---

MiR-653-5p 通过调节软骨细胞衰老驱动骨关节炎发病机制


由于骨关节炎（OA）的发病机制尚不清楚，目前尚无有效的治疗方法。越来越多的证据表明软骨细胞衰老是骨关节炎发展的关键驱动因素。本研究旨在鉴定针对软骨细胞衰老的 OA 特异性 microRNA (miRNA)，以缓解 OA 进展。我们筛选并鉴定了OA和正常软骨中差异表达的miRNA，然后通过体外过表达/沉默实验证实了miR-653-5p对软骨细胞功能和衰老表型的影响。我们确定白细胞介素6（IL-6）为miR-653-5p的靶基因，并通过功能获得/丧失研究证实了miR-653-5p对IL-6/JAK/STAT3信号通路的调节影响。最后，我们使用内侧半月板不稳定的小鼠模型评估了 miR-653-5p 对 OA 的治疗效果。 MiR-653-5p 在 OA 患者的软骨组织和软骨细胞中显着下调。 miR-653-5p 的过表达促进软骨细胞基质合成和增殖，同时抑制软骨细胞衰老。此外，生物信息学靶标预测和荧光素酶报告基因检测将 IL-6 确定为 miR-653-5p 的靶标。 Western blot检测表明，miR-653-5p过表达通过调节IL-6/JAK/STAT3信号通路抑制IL-6蛋白表达、JAK1和STAT3磷酸化以及软骨细胞衰老表型的表达。更重要的是，与对照小鼠相比，agomiR-653-5p治疗的OA小鼠模型中软骨破坏显着减轻，软骨细胞衰老表型显着降低。 MiR-653-5p 显示 OA 个体的软骨组织显着减少，导致关节软骨中软骨细胞衰老表型上调。 AgomiR-653-5p 成为 OA 的潜在治疗方法。这些发现进一步深入了解 miR-653-5p 在软骨细胞衰老和 OA 发病机制中的作用。