Osteoarthritis (OA) is a prevalent degenerative joint disease with a lack of effective therapeutic. Chondrocyte ferroptosis contributes to the progression of OA. PUM2 is shown to exacerbate ischemia–reperfusion‐induced neuroinflammation by promoting ferroptosis, but its role in OA remains unexplored. Here, primary mouse chondrocytes were stimulated with IL‐1β to mimic OA chondrocyte injury in vitro. And PUM2 was upregulated in OA cartilage tissues and IL‐1β‐induced chondrocytes. Silencing PUM2 alleviated IL‐1β‐induced chondrocyte inflammation and ECM degradation. Mechanistically, PUM2 facilitated the degradation of NEDD4 mRNA by binding to the 3′UTR of NEDD4 mRNA, which in turn inhibited NEDD4 induced PTEN ubiquitination and degradation. Consistently, NEDD4 silencing reversed the ameliorative effect of PUM2 knockdown on chondrocyte injury, and overexpression of PTEN abolished the improved role of NEDD4 in chondrocyte injury. Moreover, PTEN aggravated IL‐1β‐induced ferroptosis in chondrocytes through the Nrf2/HO‐1 pathway by increasing the levels of Fe2+, ROS, MDA, and ACSL4 protein, decreasing the activity of SOD and the levels of GSH and GPX4 protein, and aggravating mitochondrial damage. Additionally, destabilized medial meniscus (DMM) were conducted to establish the OA mouse model, and adenovirus‐mediated PUM2 shRNA was administered intra‐articularly. Silencing PUM2 attenuated OA‐induced cartilage damage in vivo. In conclusion, PUM2 promoted OA progression through PTEN‐mediated chondrocyte ferroptosis by facilitating NEDD4 mRNA degradation.

中文翻译：

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PUM2 通过促进 NEDD4 mRNA 降解，通过 PTEN 介导的软骨细胞铁死亡促进骨关节炎进展

骨关节炎（OA）是一种普遍存在的退行性关节疾病，目前缺乏有效的治疗方法。软骨细胞铁死亡有助于 OA 的进展。 PUM2 通过促进铁死亡而加剧缺血再灌注引起的神经炎症，但其在 OA 中的作用仍未被探索。在这里，用 IL-1β 刺激原代小鼠软骨细胞以模拟体外 OA 软骨细胞损伤。 PUM2 在 OA 软骨组织和 IL-1β 诱导的软骨细胞中表达上调。沉默 PUM2 可减轻 IL-1β 诱导的软骨细胞炎症和 ECM 降解。从机制上讲，PUM2通过与NEDD4 mRNA的3'UTR结合促进NEDD4 mRNA的降解，进而抑制NEDD4诱导的PTEN泛素化和降解。一致地，NEDD4沉默逆转了PUM2敲低对软骨细胞损伤的改善作用，而PTEN的过度表达消除了NEDD4在软骨细胞损伤中的改善作用。此外，PTEN 通过 Nrf2/HO-1 途径通过增加 Fe 水平，加重了 IL-1β 诱导的软骨细胞铁死亡。2+、ROS、MDA、ACSL4蛋白，降低SOD活性以及GSH、GPX4蛋白水平，加重线粒体损伤。此外，采用不稳定的内侧半月板（DMM）建立 OA 小鼠模型，并关节内注射腺病毒介导的 PUM2 shRNA。沉默 PUM2 可减轻 OA 诱导的体内软骨损伤。总之，PUM2 通过促进 NEDD4 mRNA 降解，通过 PTEN 介导的软骨细胞铁死亡促进 OA 进展。