Ferroptosis: A Frontier in Osteoporosis

Abstract

Reduced bone mass and degeneration of the microarchitecture of bone tissue are the hallmarks of osteoporosis, a bone metabolic disease that increases skeletal fragility and fracture susceptibility. Osteoporosis is primarily caused by unbalanced bone remodeling, in which bone synthesis is outpaced by bone resorption caused by osteoclasts. Along with the bone-building vitamins calcium and vitamin D, typical medications for treating osteoporosis include bisphosphonates and calcitonin. The present therapies effectively stop osteoclast activation that is too high, however they come with varying degrees of negative effects. Numerous factors can contribute to osteoporosis, which is characterized by a loss of bone mass and density due to the deterioration of the bone’s microstructure, which makes the bone more fragile. As a result, it is a systemic bone condition that makes patients more likely to fracture. Interest in the function of ferroptosis in the pathophysiology of osteoporosis is developing. In this review, we go through the shape of the cell, the fundamental mechanisms of ferroptosis, the relationship between osteoclasts and osteoblasts, the association between ferroptosis and diabetic osteoporosis, steroid-induced osteoporosis, and the relationship between ferroptosis and postmenopausal osteoporosis. The functions of ferroptosis and osteoporosis in cellular function, signaling cascades, pharmacological inhibition, and gene silencing have been better understood thanks to recent advances in biomedical research.

Keywords

osteoclasts - postmenopausal osteoporosis - osteoblasts - pathophysiology - ferroptosis

Publication History

Received: 08 September 2023

Accepted after revision: 04 December 2023

Article published online:
02 February 2024

• References

• 1 Liu J, Song X, Kuang F. et al. NUPR1 is a critical repressor of ferroptosis. Nat Commun 2021; 12: 647
• 2 Maheshwari S. Ferroptosis signaling pathways: Alzheimer’s disease. Horm Metab Res 2023; 55: 819-826
• 3 Miao Y, Chen Y, Xue F. et al. Contribution of ferroptosis and GPX4’s dual functions to osteoarthritis progression. eBioMedicine 2022; 76
• 4 Al-Hetty HR, Abdulameer SJ, Alghazali MW. et al. The role of ferroptosis in the pathogenesis of osteoarthritis. J Memb. Biol 2023; 256: 223-228
• 5 Zhou X, Zheng Y, Sun W. et al. D-mannose alleviates osteoarthritis progression by inhibiting chondrocyte ferroptosis in a HIF-2α-dependent manner. Cell Prolif 2021; 54: e13134
• 6 Yang J, Hu S, Bian Y. et al. Targeting cell death: pyroptosis, ferroptosis, apoptosis and necroptosis in osteoarthritis. Front Cell. Develop Biol 2022; 9: 789948
• 7 Liu H, Deng Z, Yu B. et al. Identification of SLC3A2 as a potential therapeutic target of osteoarthritis involved in ferroptosis by integrating bioinformatics, clinical factors and experiments. Cells 2022; 11: 3430
• 8 Distéfano AM, López GA, Bauer V. et al. Ferroptosis in plants: regulation of lipid peroxidation and redox status. Biochem J 2022; 479: 857-866
• 9 Shan K, Feng N, Zhu D. et al. Free docosahexaenoic acid promotes ferroptotic cell death via lipoxygenase dependent and independent pathways in cancer cells. Eur J Nutr 2022; 61: 4059-4075
• 10 Chen Q, Zheng Q, Yang Y. et al. 12/15-Lipoxygenase regulation of diabetic cognitive dysfunction is determined by interfering with inflammation and cell apoptosis. Int J Mol Sci 2022; 23: 8997
• 11 Mishima E, Ito J, Wu Z. et al. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature 2022; 608: 778-783
• 12 Wang X, Ma H, Sun J. et al. Mitochondrial ferritin deficiency promotes osteoblastic ferroptosis via mitophagy in type 2 diabetic osteoporosis. Biol Trace Elem Res 2022; 1: 1
• 13 Stockwell BR. et al. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell 2022; 185: 2401-2021
• 14 Xin S, Mueller C, Pfeiffer S. et al. MS4A15 drives ferroptosis resistance through calcium-restricted lipid remodeling. Cell Death Differ 2022; 29: 670-686
• 15 Forcina GC, Pope L, Murray M. et al. Ferroptosis regulation by the NGLY1/NFE2L1 pathway. Proc Natl Acad Sci 2022; 119 e2118646119
• 16 Lei G, Zhuang L, Gan B. et al. Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer 2022; 22: 381-396
• 17 Chen J, Li X, Ge C. et al. The multifaceted role of ferroptosis in liver disease. Cell Death Differ 2022; 29: 467-480
• 18 Liu Y, Gu W. et al. p53 in ferroptosis regulation: the new weapon for the old guardian. Cell Death Differ 2022; 29: 895-910
• 19 Koppula P, Lei G, Zhang Y. et al A targetable CoQ-FSP1 axis drives ferroptosis-and radiation-resistance in KEAP1 inactive lung cancers. Nat Commun 2022; 13: 2206
• 20 Liang D, Minikes AM, Jiang X. et al. Ferroptosis at the intersection of lipid metabolism and cellular signaling. Mol Cell 2022; 82: 2215-2227
• 21 Li Z, Ferguson L, Deol KK. et al. Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability. Nat Chem Biol 2022; 18: 751-761
• 22 Liu J, Kang R, Tang D. et al. Signaling pathways and defense mechanisms of ferroptosis. FEBS J 2022; 289: 7038-7050
• 23 Niu X, Chen L, Li Y. et al. Ferroptosis, necroptosis, and pyroptosis in the tumor microenvironment: perspectives for immunotherapy of SCLC. InSeminars in Cancer Biol 2022. Academic Press; New Yore: 2022
• 24 Jo A, Bae JH, Yoon YJ. et al. Plasma-activated medium induces ferroptosis by depleting FSP1 in human lung cancer cells. Cell Death Dis 2022; 13: 212
• 25 Cao F, Sang Y, Liu C. et al. Self-adaptive single-atom catalyst boosting selective ferroptosis in tumor cells. ACS Nano 2022; 16: 855-868
• 26 Chen X, Huang J, Yu C. et al. A noncanonical function of EIF4E limits ALDH1B1 activity and increases susceptibility to ferroptosis. Nat Commun 2022; 13: 6318
• 27 Pan WL, Tan Y, Meng W. et al. Microenvironment-driven sequential ferroptosis, photodynamic therapy, and chemotherapy for targeted breast cancer therapy by a cancer-cell-membrane-coated nanoscale metal-organic framework. Biomaterials 2022; 283: 121449
• 28 Wang Y, Yan S, Liu X. et al. PRMT4 promotes ferroptosis to aggravate doxorubicin-induced cardiomyopathy via inhibition of the Nrf2/GPX4 pathway. Cell Death Differ 2022; 29: 1982-1995
• 29 Tan Y, Huang Y, Mei R. et al. HucMSC-derived exosomes delivered BECN1 induces ferroptosis of hepatic stellate cells via regulating the xCT/GPX4 axis. Cell Death Disease 2022; 13: 319
• 30 Wang WJ, Ling YY, Zhong YM. et al. Ferroptosis-enhanced cancer immunity by a ferrocene-appended iridium (III) Diphosphine complex. Angew Chem 2022; 134 e202115247
• 31 Yuan S, Wei C, Liu G. et al. Sorafenib attenuates liver fibrosis by triggering hepatic stellate cell ferroptosis via HIF-1α/SLC7A11 pathway. Cell Prolifer 2022; 55: e13158
• 32 Cui J, Zhou Q, Yu M. et al. 4-tert-butylphenol triggers common carp hepatocytes ferroptosis via oxidative stress, iron overload, SLC7A11/GSH/GPX4 axis, and ATF4/HSPA5/GPX4 axis. Ecotoxicol Environmen Safety 2022; 242: 13944
• 33 Yan HF, Zou T, Tuo QZ. et al. Ferroptosis: mechanisms and links with diseases. Signal Transduc Target Ther 2021; 6: 49
• 34 Weiland A, Wang Y, Wu W. et al. Ferroptosis and its role in diverse brain diseases. Mol Neurobiol 2019; 56: 880-893
• 35 Weiland A, Wang Y, Wu W. et al. Ferroptosis and its role in diverse brain diseases. Mol Neurobiol 2019; 56: 4880-4893
• 36 Vitalakumar D, Sharma A, Flora SJ. et al. Ferroptosis: a potential therapeutic target for neurodegenerative diseases. J Biochem Mol Toxicol 2021; 35: e22830
• 37 Li N, Yi X, He Y. et al. Targeting ferroptosis as a novel approach to alleviate aortic dissection. Int J Biol Sci 2022; 18: 4118-4134
• 38 Lei J, Chen Z, Song S. et al. Insight into the role of ferroptosis in non-neoplastic neurological diseases. Front Cell Neurosci 2020; 14: 231
• 39 Cheng Y, Song Y, Chen H. et al. Ferroptosis mediated by lipid reactive oxygen species: a possible causal link of neuroinflammation to neurological disorders. Oxidative Med Cell Longev 2021;
• 40 Sun Y, Yan C, He L. et al. Inhibition of ferroptosis through regulating neuronal calcium homeostasis: An emerging therapeutic target for Alzheimer’s disease. Ageing Res Rev 2023; 87: 101899
• 41 Tang M, Chen Z, Wu D. et al. Ferritinophagy/ferroptosis: iron-related newcomers in human diseases. J Cell Physiol 2018; 233: 9179-9190
• 42 Qiu Y, Cao Y, Cao W. et al. The application of ferroptosis in diseases. Pharmacol Res 2020; 159: 104919
• 43 Rogers JT, Cahill CM. et al. Iron-responsive-like elements and neurodegenerative ferroptosis. Learn Mem 2020; 27: 395-413
• 44 Stockwell BR, Angeli JP, Bayir H. et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 2017; 171: 273-285
• 45 Wang S, Liao H, Li F. et al. A mini-review and perspective on ferroptosis-inducing strategies in cancer therapy. Chin Chem Lett 2019; 30: 847-852
• 46 Musheshe N, Oun A, Sabogal-Guáqueta AM. et al. Pharmacological inhibition of epac1 averts ferroptosis cell death by preserving mitochondrial integrity. Antioxidants 2022; 11: 314
• 47 Plascencia-Villa G, Perry G. et al. Implication of ferroptosis iron-dependent programmed cell death mechanism in neurodegeneration: molecular and cell biology/oxidative stress. Alzheimer Dement 2020; 16: e043978
• 48 Li J, Li M, Ge Y. et al. β-amyloid protein induces mitophagy-dependent ferroptosis through the CD36/PINK/PARKIN pathway leading to blood–brain barrier destruction in Alzheimer’s disease. Cell Biosci 2022; 12: 69
• 49 Sun W, Yan J, Ma H. et al. Autophagy-dependent ferroptosis-related signature is closely associated with the prognosis and tumor immune escape of patients with glioma. Int J Gen Med 2022; 253-270
• 50 Liu L, Yang S, Wang H. et al. α-Lipoic acid alleviates ferroptosis in the MPP+-induced PC12 cells via activating the PI3K/Akt/Nrf2 pathway. Cell Biol Int 2021; 45: 422-431
• 51 Wu L, Xian X, Tan Z. et al. The Role of iron metabolism, lipid metabolism, and redox homeostasis in Alzheimer’s disease: from the perspective of ferroptosis. Mol Neurobiol 2023; 1-9
• 52 Hassannia B, Van Coillie S, Vanden Berghe T. et al. Ferroptosis: biological rust of lipid membranes. Antioxid Redox Signal 2021; 35: 487-509
• 53 Lei G, Zhang Y, Hong T. et al. Ferroptosis as a mechanism to mediate p53 function in tumor radiosensitivity. Oncogene 2021; 40: 3533-3547
• 54 Zhou X, Tang X, Li T. et al. Inhibition of VDAC1 rescues Aβ 1-42-induced mitochondrial dysfunction and ferroptosis via activation of AMPK and Wnt/β-catenin pathways. Mediators Inflamm 2023; 6739691
• 55 Reichert CO, de Freitas FA, Sampaio-Silva J. et al. Ferroptosis mechanisms involved in neurodegenerative diseases. Int J Mol Sci 2020; 21: 8765
• 56 Xie Z, Wang X, Luo X. et al. Activated AMPK mitigates diabetes-related cognitive dysfunction by inhibiting hippocampal ferroptosis. Biochem Pharmacol 2023; 207: 115374
• 57 Wang X, Liu Z, Peng P. et al. Astaxanthin attenuates osteoarthritis progression via inhibiting ferroptosis and regulating mitochondrial function in chondrocytes. Chem Biol Interact 2022; 366: 110148
• 58 Wan Y, Yu H, Fan W. et al. Baicalein limits osteoarthritis development by inhibiting chondrocyte ferroptosis. Free Rad. Biol Med 2023; 196: 108-120
• 59 Lv M, Cai Y, Hou W. et al. The RNA-binding protein SND1 promotes the degradation of GPX4 by destabilizing the HSPA5 mRNA and suppressing HSPA5 expression, promoting ferroptosis in osteoarthritis chondrocytes. Inflamm Res 2022; 71: 461-472
• 60 Xu W, Zhang B, Xi C. et al. Ferroptosis plays a role in human chondrocyte of osteoarthritis induced by IL-1β in vitro. Cartilage. 2023 19476035221142011
• 61 Riegger J. TRPV1 as an anti-ferroptotic target in osteoarthritis. eBioMedicine 2022; 84: 104279
• 62 Lv Z, Han J, Li J. et al. Single cell RNA-seq analysis identifies ferroptotic chondrocyte cluster and reveals TRPV1 as an anti-ferroptotic target in osteoarthritis. eBioMedicine 2022; 84: 104258
• 63 Gao L, Hua W, Tian L. et al. Molecular mechanism of ferroptosis in orthopedic diseases. Cells 2022; 11: 2979
• 64 Lu J, Yang J, Zheng Y. et al. Extracellular vesicles from endothelial progenitor cells prevent steroid-induced osteoporosis by suppressing the ferroptotic pathway in mouse osteoblasts based on bioinformatics evidence. Sci Rep 2019; 9: 16130
• 65 Zhang Y, Han S, Kong M. et al. Single-cell RNA-seq analysis identifies unique chondrocyte subsets and reveals involvement of ferroptosis in human intervertebral disc degeneration. Osteoarthr Cartil 2021; 29: 1324-1334
• 66 Luo H, Zhang R. et al. Icariin enhances cell survival in lipopolysaccharide-induced synoviocytes by suppressing ferroptosis via the Xc-/GPX4 axis. Exp Ther Med 2021; 21: 72
• 67 Zhou M, Zhai C, Shen K. et al. miR-1 Inhibits the Ferroptosis of Chondrocyte by Targeting CX43 and Alleviates Osteoarthritis Progression. J Immunol Res 2023;
• 68 Xiong Z, Sun H, Liu M. et al. Roles of ferroptosis in intervertebral disc degeneration and osteoarthritis. Chin J Tissue Eng Res 2023; 27: 5884
• 69 Xu G, Lu M, Fang L. et al. Quercetin suppresses ferroptosis in chondrocytes via activating the Nrf2/GPX4 signaling pathway. Nat Prod Commun 2023; 18 1934578X231194837
• 70 Xu W, Mei Q, Yuan C. et al. Identifying characteristic genes of ferroptosis in osteoarthritis based on machine learning and analysis of immune infiltration. Res Square 2023;
• 71 Guo Z, Lin J, Sun K. et al. Corrigendum: Deferoxamine alleviates osteoarthritis by inhibiting chondrocyte ferroptosis and activating the Nrf2 pathway. Front Pharmacol 2023; 14: 1199951
• 72 He Q, Yang J, Pan Z. et al. Biochanin A protects against iron overload associated knee osteoarthritis via regulating iron levels and NRF2/System xc-/GPX4 axis. Biomed Pharmacother 2023; 157: 113915
• 73 Han T, Zhang Y, Qi B. et al. Clinical features and shared mechanisms of chronic gastritis and osteoporosis. Sci Rep 2023; 13: 4991
• 74 Zhou LP, Zhang RJ, Jia CY. et al. Ferroptosis: A potential target for the intervention of intervertebral disc degeneration. Front Endocrinol 2022; 13: 1042060
• 75 Li Y, Meng L, Zhao B. et al. The roles of N6-methyladenosine methylation in the regulation of bone development, bone remodeling and osteoporosis. Pharmacol Ther 2022; 238: 108174
• 76 Li M, He Q, Zeng J. et al. Iron overload in bone diseases. Chin J Tissue Eng Res 2023; 27: 2723
• 77 Li Y, Li F. et al. Mechanism and prospect of gastrodin in osteoporosis, bone regeneration, and osseointegration. Pharmaceuticals 2022; 15: 1432
• 78 Hu W, Liang K, Zhu H. et al. Ferroptosis and its role in chronic diseases. Cells 2022; 11: 2040
• 79 Miao R, Fang X, Zhang Y. et al. Iron metabolism and ferroptosis in type 2 diabetes mellitus and complications: mechanisms and therapeutic opportunities. Cell Death Dis 2023; 14: 186
• 80 Chang S, Tang M, Zhang B. et al. Ferroptosis in inflammatory arthritis: A promising future. Front Immunol 2022; 13: 955069