Osteoporotic bone loss from excess iron accumulation is driven by NOX4-triggered ferroptosis in osteoblasts

Hui Zhang; Aifei Wang; Guangfei Li; Qiaocheng Zhai; Zhengyun Huang; Xiao Wang; Zihou Cao; Lulin Liu; Gongwen Liu; Bin Chen; Keyu Zhu; Ying Xu; Youjia Xu

doi:10.1016/j.freeradbiomed.2023.01.026

Osteoporotic bone loss from excess iron accumulation is driven by NOX4-triggered ferroptosis in osteoblasts

Free Radic Biol Med. 2023 Mar:198:123-136. doi: 10.1016/j.freeradbiomed.2023.01.026. Epub 2023 Feb 3.

Authors

Hui Zhang¹, Aifei Wang², Guangfei Li³, Qiaocheng Zhai⁴, Zhengyun Huang⁴, Xiao Wang³, Zihou Cao⁵, Lulin Liu⁶, Gongwen Liu⁷, Bin Chen³, Keyu Zhu², Ying Xu⁸, Youjia Xu⁹

Affiliations

¹ Department of Orthopaedics, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China; Department of Orthopaedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Osteoporosis Clinical Center, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
² Department of Orthopaedics, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China; Osteoporosis Clinical Center, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China; Institute of Osteoporosis Diagnosis and Treatments of Soochow University, Suzhou, 215004, China.
³ Department of Orthopaedics, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China; Osteoporosis Clinical Center, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
⁴ Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Su Genomic Resource Center, Medical School of Soochow University, Suzhou, Jiangsu, 215123, China.
⁵ Department of Orthopaedics, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China; Institute of Osteoporosis Diagnosis and Treatments of Soochow University, Suzhou, 215004, China.
⁶ Institute of Osteoporosis Diagnosis and Treatments of Soochow University, Suzhou, 215004, China.
⁷ Department of Orthopaedics, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, 215004, China.
⁸ Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Su Genomic Resource Center, Medical School of Soochow University, Suzhou, Jiangsu, 215123, China. Electronic address: yingxu@suda.edu.cn.
⁹ Department of Orthopaedics, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China; Osteoporosis Clinical Center, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China; Institute of Osteoporosis Diagnosis and Treatments of Soochow University, Suzhou, 215004, China. Electronic address: xuyoujia@suda.edu.cn.

PMID: 36738798
DOI: 10.1016/j.freeradbiomed.2023.01.026

Abstract

Excess iron accumulation is a risk factor for osteopenia and osteoporosis, and ferroptosis is becoming well understood as iron-dependent form of cell death resulting from lipid peroxide accumulation. However, any pathological impacts of ferroptosis on osteoporosis remain unknown. Here, we show that ferroptosis is involved in excess-iron-induced bone loss and demonstrate that osteoporotic mice and humans have elevated skeletal accumulation of the NADPH oxidase 4 (NOX4) enzyme. Mechanistically, we found that the NOX4 locus contains iron-response element-like (IRE-like) sequences that are normally bound (and repressed) by the iron regulatory protein 1 (IRP1) protein. Binding with iron induces dissociation of IRP1 from the IRE-like sequences and thereby activates NOX4 transcription. Elevated NOX4 increases lipid peroxide accumulation and causes obvious dysregulation of mitochondrial morphology and function in osteoblasts. Excitingly, the osteoporotic bone loss which we initially observed in an excessive-iron accumulating mouse line (Hepc1^-/-) was blocked upon treatment with the ferroptosis-inhibitor ferrostatin-1 (Ferr-1) and with the iron chelator deferoxamine (DFO), suggesting a potential therapeutic strategy for preventing osteoporotic bone loss based on disruption of ferroptosis.

Keywords: Ferroptosis; GPX4; Iron; NOX4; Osteoblast; Osteoporosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Ferroptosis*
Humans
Iron / metabolism
Iron Overload*
Lipid Peroxides
Mice
NADPH Oxidase 4 / metabolism
Osteoblasts / metabolism
Osteoporosis*

Substances

NADPH Oxidase 4
Lipid Peroxides
Iron
NOX4 protein, human
Nox4 protein, mouse