铁死亡与骨质疏松症

Ferroptosis and osteoporosis

背景:已证实铁死亡与多种骨骼肌肉疾病密切相关,例如类风湿关节炎、骨肉瘤、骨质疏松症等。而铁死亡和骨质疏松症的病理生理机制有待进一步研究和阐明,以拓宽对铁代谢和骨质疏松症的认识,为今后阐明骨质疏松的新机制、开发治疗骨质疏松的新技术和新药提供研究思路。目的:对铁死亡在骨质疏松症中的研究现状展开综述,为未来研究骨质疏松症的具体分子机制提供一条新方向,为骨质疏松症的治疗策略提供更有效、更好的选择。方法:由第一作者应用计算机检索2000-2024年出版的文献,以“铁死亡,铁代谢,骨质疏松,成骨细胞,破骨细胞,骨代谢,信号通路,肌肉骨骼,综述”等为中文检索词检索中国知网、万方和维普数据库;以“ferroptosis,iron metabolism,osteoporosis,osteoblast,osteoclast,bone metabolism,signal pathway,musculoskeletal,review”等为英文检索词检索PubMed数据库,按照入选标准最终共纳入68篇文献。结果与结论:①铁死亡是近年来发现的一种新的细胞死亡类型,通常伴随着细胞死亡过程中的大量铁积累和脂质过氧化,其发生具有铁依赖性,这与目前研究较热的几种细胞死亡方式(例如细胞焦亡、坏死性凋亡、铜死亡、自噬)有明显的区别。②细胞内铁稳态表现为铁的吸收、输出、利用和储存之间的平衡。人体的铁调节系统包括全身调节和细胞内调节,系统调节的主要因子是肝分泌产生的铁调节激素,细胞调节依赖于铁调节蛋白/铁反应元件系统;当然,细胞内铁稳态还可以由其他因素控制,例如缺氧、细胞因子和激素等。③脂质过氧化反应会对生物膜(质膜和内部细胞器膜)、脂蛋白和其他含脂质的分子造成氧化损伤。多不饱和脂肪酸磷脂是脂质过氧化的重要靶点,游离多不饱和脂肪酸是脂质氧化的重要底物,可与磷脂双分子层结合,导致过度氧化,从而引发脂质凋亡。④多项研究表明,通过不同的方式使成骨细胞铁超载,致细胞内不稳定的亚铁不断积累并产生活性氧和脂质过氧化物,造成成骨细胞铁死亡,最终引起骨形成减少影响骨稳态发生骨质疏松。⑤破骨细胞是由单核巨噬细胞系或骨髓间充质干细胞在核因子κB配体受体激活因子诱导下融合形成的大型多核细胞,具有骨吸收功能。铁离子可通过产生细胞内脂质活性氧促进破骨细胞分化和骨吸收,而铁螯合剂在体外可以抑制破骨细胞形成进而影响骨质疏松症的发生发展。

BACKGROUND:It has also been confirmed that ferroptosis is closely related to a variety of musculoskeletal diseases,such as rheumatoid arthritis,osteosarcoma,and osteoporosis.The pathophysiological mechanisms of ferroptosis and osteoporosis need to be further studied and elucidated to broaden our understanding of iron metabolism and osteoporosis.It will provide research ideas for the future elucidation of new mechanisms of osteoporosis and the development of new technologies and drugs for the treatment of osteoporosis.OBJECTIVE:To provide an overview of the current status of research on ferroptosis in osteoporosis,to provide a new direction for future research on the specific molecular mechanisms of osteoporosis,and to provide more effective and better options for osteoporosis treatment strategies.METHODS:The first author used the computer to search the literature published from 2000 to 2024 in CNKI,WanFang,VIP,and PubMed databases with search terms“ferroptosis,iron metabolism,osteoporosis,osteoblast,osteoclast,bone metabolism,signal pathway,musculoskeletal,review”in Chinese and English.A total of 68 articles were finally included according to the selection criteria.RESULTS AND CONCLUSION:(1)Ferroptosis is a new type of cell death discovered in recent years,which is usually accompanied by a large amount of iron accumulation and lipid peroxidation during cell death,and its occurrence is iron-dependent.This is distinctly different from several types of cell death that are currently being hotly studied(e.g.,cellular pyroptosis,necrotic apoptosis,cuproptosis,and autophagy).(2)Intracellular iron homeostasis is manifested as a balance between iron uptake,export,utilization,and storage.The body’s iron regulatory system includes systemic and intracellular regulation.The main factor of systemic regulation is hepcidin produced by hepatic secretion,and cellular regulation depends on the iron regulatory protein/iron response element system.Of course,intracellular iron homeostasis can be controlled by other factors,such as hypoxia,cytokines,and hormones.(3)Lipid peroxidation causes oxidative damage to biological membranes(plasma membrane and internal organelle membranes),lipoproteins,and other lipid-containing molecules.Polyunsaturated fatty acid-containing phospholipids are important targets of lipid peroxidation.Free polyunsaturated fatty acid is an important substrate for lipid oxidation and can bind to the phospholipid bilayer,leading to over-oxidation and thus triggering lipid apoptosis.(4)Several studies have shown that osteoblasts are overloaded with iron in different ways,resulting in the accumulation of unstable ferrous iron and the generation of reactive oxygen species and lipid peroxides,causing ferroptosis of osteoblasts and ultimately a decrease in bone formation,affecting bone homeostasis and the development of osteoporosis.(5)Osteoclasts are large multinucleated cells formed by the fusion of mononuclear macrophage cell lines or bone marrow mesenchymal stem cells induced by nuclear factor-κB ligand receptor activator,and they have the function of bone resorption.Iron ions can promote osteoclast differentiation and bone resorption through the production of intracellular lipid reactive oxygen species,while iron chelators can inhibit osteoclast formation in vitro and thus affect the occurrence and development of osteoporosis.