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

Humans Mice Animals Ferroptosis NADPH Oxidase 4 / metabolism Lipid Peroxides Iron / metabolism Iron Overload Osteoporosis Osteoblasts / metabolism
Ferroptosis GPX4 Iron NOX4 Osteoblast Osteoporosis

Journal

Free radical biology & medicine
ISSN: 1873-4596
Titre abrégé: Free Radic Biol Med
Pays: United States
ID NLM: 8709159

Informations de publication

Date de publication:
03 2023
Historique:
received: 12 09 2022
revised: 08 01 2023
accepted: 29 01 2023
pubmed: 5 2 2023
medline: 3 3 2023
entrez: 4 2 2023
Statut: ppublish

Résumé

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

Identifiants

DOI: 10.1016/j.freeradbiomed.2023.01.026 PMID: 36738798
pubmed: 36738798
pii: S0891-5849(23)00044-8
doi: 10.1016/j.freeradbiomed.2023.01.026
pii:
doi:

Substances chimiques

NADPH Oxidase 4 EC 1.6.3.-
Lipid Peroxides 0
Iron E1UOL152H7
NOX4 protein, human EC 1.6.3.-
Nox4 protein, mouse EC 1.6.3.-

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

123-136

Informations de copyright

Copyright © 2023 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare no competing interests.

Auteurs

Hui Zhang (H)

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.

Aifei Wang (A)

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.

Guangfei Li (G)

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.

Qiaocheng Zhai (Q)

Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Su Genomic Resource Center, Medical School of Soochow University, Suzhou, Jiangsu, 215123, China.

Zhengyun Huang (Z)

Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Su Genomic Resource Center, Medical School of Soochow University, Suzhou, Jiangsu, 215123, China.

Xiao Wang (X)

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.

Zihou Cao (Z)

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.

Lulin Liu (L)

Institute of Osteoporosis Diagnosis and Treatments of Soochow University, Suzhou, 215004, China.

Gongwen Liu (G)

Department of Orthopaedics, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, 215004, China.

Bin Chen (B)

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.

Keyu Zhu (K)

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.

Ying Xu (Y)

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.

Youjia Xu (Y)

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.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Osteoporotic bone loss from excess iron...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Osteoporotic bone loss from excess iron...
questionsmedicales.fr › Eucaryotes › Animaux › Osteoporotic bone loss from excess iron...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Mort cellulaire › Mort cellulaire régulée › Ferroptose › Osteoporotic bone loss from excess iron...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › NADPH oxidase › NADPH Oxidase 4 › Osteoporotic bone loss from excess iron...
questionsmedicales.fr › Lipides › Peroxydes lipidiques › Osteoporotic bone loss from excess iron...
questionsmedicales.fr › Produits chimiques inorganiques › Métaux › Métaux lourds › Fer › Osteoporotic bone loss from excess iron...
questionsmedicales.fr › Maladies métaboliques et nutritionnelles › Maladies métaboliques › Troubles du métabolisme du fer › Surcharge en fer › Osteoporotic bone loss from excess iron...
questionsmedicales.fr › Maladies métaboliques et nutritionnelles › Maladies métaboliques › Maladies osseuses métaboliques › Ostéoporose › Osteoporotic bone loss from excess iron...
questionsmedicales.fr › Cellules › Cellules du tissu conjonctif › Ostéoblastes › Osteoporotic bone loss from excess iron...