Xie Ya, Lv Zhongyang, Li Weitong, Lin JinTao, Sun Wei, Guo Hu, Jin Xiaoyu, Liu Yuan, Jiang Ruiyang, Fei Yuxiang, Wu Rui, Shi Dongquan
Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China.
Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China.
J Orthop Translat. 2025 Mar 8;51:132-144. doi: 10.1016/j.jot.2025.01.001. eCollection 2025 Mar.
Osteoarthritis (OA) is the most common degenerative joint disease, and its main pathological mechanism is articular cartilage degeneration. The purpose of this study was to investigate the role of mitophagy in the pathogenesis of chondrocyte ferroptosis in OA.
The expressions of ferroptosis related proteins (GPX4, FTH1, COX2) and ubiquitin-dependent mitophagy related proteins (PARKIN, PINK1) in the intact and injured areas of OA cartilage were analyzed. Nitro oxide JP4-039, a mitochondrial targeting antioxidant, has bifunctional role of targeting mitochondria. Then we evaluated the potential protective effect of JP4-039 in OA using the destabilization of medial meniscus (DMM)-induced OA model, as well as tert-butyl hydrogen peroxide (TBHP)-treated primary mouse chondrocytes and human cartilage explants.
The concentrations of iron and lipid peroxidation and the expression of ferroptosis drivers in the damaged areas of human OA cartilages were significantly higher than those in the intact cartilage. Pink1/Parkin-dependent mitophagy decreased in the injured area of human OA cartilage and was negatively correlated with ferroptosis. Then, the toxicity and effectiveness of JP4-039 are tested to determine its working concentration. Next, at the molecular biological level, we found that JP4-039 showed the effect of anti-chondrocyte ferroptosis. Moreover, it was verified on DMM-induced OA model mice, that JP4-039 could delay the progression of OA. Finally, JP4-039 was re-verified in vivo and in vitro to inhibit chondrocyte ferroptosis and delay the progression of OA by promoting Pink1/Parkin-dependent mitophagy.
JP4-039 inhibits ferroptosis of chondrocytes by promoting Pink1/Parkin-dependent mitophagy and delays OA progression.
骨关节炎（OA）是最常见的退行性关节疾病，其主要病理机制是关节软骨退变。本研究旨在探讨线粒体自噬在OA软骨细胞铁死亡发病机制中的作用。
分析OA软骨完整区域和损伤区域中铁死亡相关蛋白（GPX4、FTH1、COX2）及泛素依赖性线粒体自噬相关蛋白（PARKIN、PINK1）的表达。线粒体靶向抗氧化剂一氧化氮JP4-039具有靶向线粒体的双重功能。然后，我们使用内侧半月板不稳定（DMM）诱导的OA模型，以及叔丁基过氧化氢（TBHP）处理的原代小鼠软骨细胞和人软骨外植体，评估JP4-039对OA的潜在保护作用。
人OA软骨损伤区域的铁浓度、脂质过氧化水平及铁死亡驱动因子的表达均显著高于完整软骨。Pink1/Parkin依赖性线粒体自噬在人OA软骨损伤区域减少，且与铁死亡呈负相关。接着，测试了JP4-039的毒性和有效性以确定其工作浓度。接下来，在分子生物学水平上，我们发现JP4-039具有抗软骨细胞铁死亡的作用。此外，在DMM诱导的OA模型小鼠上证实，JP4-039可延缓OA的进展。最后，在体内和体外再次验证JP4-039通过促进Pink1/Parkin依赖性线粒体自噬抑制软骨细胞铁死亡并延缓OA的进展。
JP4-039通过促进Pink1/Parkin依赖性线粒体自噬抑制软骨细胞铁死亡并延缓OA进展。
