Ferroptosis in osteogenic differentiation: a narrative review of bone regeneration metabolism

Huang, Lei1,#; Wang, Jiayi2,#; Xu, Jin3; Bian, Mengxuan4; Wang, Jianjie1,*; Lu, Shunyi5,*

1Department of Orthopedic Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai, China

2Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China

3Faculty of Medicine, Ludwig-Maximilians-University Munich, Munich, Germany

4Department of Orthopedic Surgery, The Fourth Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China

5Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China

*Correspondence to: Jianjie Wang, wjj034370@163.com; Shunyi Lu, lushunyi@suda.edu.cn.

#Both authors contributed equally to this work and share first authorship.

Abstract

Bone healing is a complex multifactor and diverse physiological process. In terms of osteogenic differentiation, different types of regulated cell death, such as ferroptosis, play key roles in the bone microenvironment. Ferroptosis is a new type of regulated cell death discovered in 2012. It is characterized by lipid peroxidation and iron-dependent accumulation, which are closely related to various clinical challenges. In recent years, an increasing number of studies have indicated a strong potential relationship between ferroptosis and different orthopedic diseases, including osteoporosis, osteopenia and osteoarthritis. Hence, an in-depth investigation of the relationship between ferroptosis and bone metabolism is highly important for the treatment of orthopedic diseases. Moreover, ferroptosis is also accompanied by morphological changes in mitochondria, such as increased membrane density and shrunken mitochondria, which have been detected in osteoblasts, bone marrow stem mesenchymal cells and osteoclasts. The inhibition of ferroptosis can reduce mitochondrial damage, alleviate oxidative stress and promote bone regeneration. This article reviews the mechanism of ferroptosis from the aspects of iron overload and the regulation of ferroptosis-related pathways, as well as their effects on bone regeneration. Increasing evidence has shown that bone defect healing and bone regeneration processes are closely related to abnormal iron metabolism. Inhibiting ferroptosis in BMSCs or OBs can effectively improve the bone healing rate and promote bone regeneration progression. The regulation of ferroptosis plays an important role in osteogenic differentiation. We discuss the detailed mechanism of ferroptosis and summarize the current research on ferroptosis and bone disease treatment.

骨再生代谢相关成骨分化中的铁死亡：叙述性综述

摘要

骨愈合是一个复杂的多因素、多样化的生理过程。对于成骨分化而言，不同的调控细胞死亡模式在骨微环境中发挥着关键作用，例如铁死亡。铁死亡是一种调节性细胞死亡模式，它以脂质过氧化和铁依赖性积累为特征，与各种临床难题密切相关。近年来，越来越多的研究表明，铁死亡与骨质疏松症、骨质增生或骨关节炎等骨科疾病之间存在密切的潜在关系。因此，深入研究铁死亡与骨代谢之间的关系对骨科疾病的治疗具有重要意义。此外，铁死亡还伴随着线粒体的形态变化，如膜密度增加和线粒体萎缩，这已在成骨细胞、骨髓干间质细胞或破骨细胞中检测到。抑制铁死亡可减少线粒体损伤，减轻氧化应激，促进骨再生。文章从铁过载、铁死亡相关通路的调控及其对骨再生的影响等方面综述了铁变态反应的机制。越来越多的证据表明，骨缺损愈合和骨再生过程与铁代谢异常密切相关。抑制骨髓间充质干细胞或成骨细胞的铁死亡可有效提高骨愈合率，促进骨再生进程。铁死亡的调控在成骨分化过程中起着重要作用，需要进行广泛的研究以建立对这一过程的理论认知，并在未来开发出有前景的治疗策略。