JP4-039 protects chondrocytes from ferroptosis to attenuate osteoarthritis progression by promoting Pink1/Parkin-dependent mitophagy

IF 5.9 1区医学 Q1 ORTHOPEDICS

Journal of Orthopaedic Translation Pub Date : 2025-03-01 DOI:10.1016/j.jot.2025.01.001

Ya Xie , Zhongyang Lv , Weitong Li , JinTao Lin , Wei Sun , Hu Guo , Xiaoyu Jin , Yuan Liu , Ruiyang Jiang , Yuxiang Fei , Rui Wu , Dongquan Shi

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Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

JP4-039 inhibits ferroptosis of chondrocytes by promoting Pink1/Parkin-dependent mitophagy and delays OA progression.

Abstract Image

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JP4-039通过促进Pink1/帕金森依赖的线粒体自噬，保护软骨细胞免于铁下垂，从而减缓骨关节炎的进展

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。本研究的目的是探讨线粒体自噬在骨性关节炎软骨细胞下垂的发病机制中的作用。方法分析OA软骨完整区和损伤区铁凋亡相关蛋白（GPX4、FTH1、COX2）和泛素依赖性线粒体自噬相关蛋白（PARKIN、PINK1）的表达。一氧化氮JP4-039是一种线粒体靶向抗氧化剂，具有靶向线粒体的双重功能。然后，我们通过破坏内侧半月板（DMM）诱导的OA模型，以及过氧化叔丁基氢（TBHP）处理的小鼠原代软骨细胞和人软骨外植体，评估JP4-039对OA的潜在保护作用。结果OA软骨损伤区铁、脂质过氧化浓度及铁下垂驱动因子的表达明显高于OA软骨损伤区。人OA软骨损伤区Pink1/ parkinson依赖性线粒体自噬减少，与铁下垂呈负相关。然后对JP4-039的毒性和有效性进行测试，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具有抗软骨细胞铁下垂的作用。此外，在dmm诱导的OA模型小鼠上验证了JP4-039可以延缓OA的进展。最后，在体内和体外再次验证JP4-039通过促进Pink1/ parkinson依赖性线粒体自噬来抑制软骨细胞铁下垂并延缓OA的进展。结论jp4 -039通过促进Pink1/ parkinson依赖性线粒体自噬，延缓骨性关节炎进展，抑制软骨细胞铁下垂。

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来源期刊

Journal of Orthopaedic Translation Medicine-Orthopedics and Sports Medicine

CiteScore

11.80

自引率

13.60%

发文量

审稿时长

29 days

期刊介绍： The Journal of Orthopaedic Translation (JOT) is the official peer-reviewed, open access journal of the Chinese Speaking Orthopaedic Society (CSOS) and the International Chinese Musculoskeletal Research Society (ICMRS). It is published quarterly, in January, April, July and October, by Elsevier.