铁死亡在椎间盘退变和骨关节炎中的作用

Roles of ferroptosis in intervertebral disc degeneration and osteoarthritis

背景:铁死亡是一种区别于凋亡、自噬和焦亡的程序性死亡,其发生与铁离子依赖性多不饱和脂肪酸过氧化相关。近几年的研究表明铁死亡与椎间盘退变和骨关节炎的发生发展密切相关。目的:总结铁死亡的发生机制及其在椎间盘退变及骨关节炎进展中的作用,以期为椎间盘退变和骨关节炎提供新的治疗策略。方法:以PubMed、万方数据和中国知网数据库为文献来源。中文检索词为:“椎间盘退变;骨关节炎;髓核;软骨细胞;关节软骨;铁死亡”,英文检索词为:“intervertebral disc degeneration;osteoarthritis;nucleus pulposus;chondrocyte;articular cartilage;ferroptosis”。最终筛选67篇文章进行综述。结果与结论:(1)铁死亡为新近发现的一种细胞程序性死亡,其发生机制与铁离子异常积蓄、多不饱和脂肪酸过氧化、氨基酸异常代谢、线粒体功能失调和铁蛋白自噬等因素密切相关。(2)各种刺激因素如同型半胱氨酸、过氧化氢叔丁醇和柠檬酸铁铵等主要通过抑制谷胱甘肽过氧化物酶4活性,引起髓核细胞、纤维环细胞和终板软骨细胞铁死亡,从而促进椎间盘退变。此外,铁死亡在椎间盘退变中的作用受miRNA的调控。(3)铁死亡通过参与软骨细胞丢失、细胞外基质溶解和滑膜炎促进骨关节炎的进展。软骨细胞铁死亡可被豆甾醇、D-甘露糖、虾青素、二甲双胍和淫羊藿苷等所抑制,而白细胞介素1β、柠檬酸铁铵和RNA结合蛋白SND1可加剧铁死亡的发生。(4)一些针对铁死亡的药物如去铁胺、铁死亡抑制剂等对椎间盘退变和骨关节炎的治疗效果已经在实验中得到验证,但还未在临床上应用。随着研究不断深入,抑制铁死亡发生可为椎间盘退变和骨关节炎的治疗和预防提供一种新的有效策略。

BACKGROUND:Ferroptosis is a new type of programmed cell death,distinguished from apoptosis,autophagy and pyroptosis,which is characterized by the iron-dependent accumulation of polyunsaturated fatty acid peroxidation.Studies in recent years have shown that ferroptosis is closely associated with the development of intervertebral disc degeneration and osteoarthritis.OBJECTIVE:To review the action mechanism of ferroptosis and its role in intervertebral disc degeneration and osteoarthritis progression,and provide new therapeutic strategies for intervertebral disc degeneration and osteoarthritis.METHODS:Pub Med,WanFang and CNKI databases were used as the literature sources.The search terms were“intervertebral disc degeneration;osteoarthritis;nucleus pulposus;chondrocytes;articular cartilage;ferroptosis”in English and Chinese.Finally,67 articles were screened for this review.RESULTS AND CONCLUSION:(1)Ferroptosis is a newly discovered programmed cell death,whose mechanism is closely related to the factors such as abnormal iron ion accumulation,polyunsaturated fatty acid peroxidation,abnormal amino acid metabolism,mitochondrial dysfunction,and ferritin autophagy.(2)Various stimulation factors such as homocysteine,tert-buty1 hydroperoxide and ferric ammonium citrate mainly through inhibiting glutathione peroxidase 4 activity cause ferroptosis of nucleus pulposus cells,annulus fibrosus cells,and chondrocytes of the endplate chondrocytes,thus promoting intervertebral disc degeneration.In addition,the role of ferroptosis in intervertebral disc degeneration is regulated by miRNA.(3)Ferroptosis promotes the progression of osteoarthritis by participating in chondrocyte loss,extracellular matrix lysis,and synovitis.Chondrocyte ferroptosis is inhibited by stigmasterol,D-mannose,astaxanthin,metformin and icariin,while it is exacerbated by interleukin-1β,ferric ammonium citrate and RNA binding protein SND1.(4)The therapeutic effects of some drugs targeting ferroptosis,such as deferoxamine,ferroptosis inhibitor,on intervertebral disc degeneration and osteoarthritis,have been verified by experiment,but have not been applied clinically.With the deepening of research,inhibiting the occurrence of ferroptosis can provide a new and effective strategy for the treatment and prevention of intervertebral disc degeneration and osteoarthritis.