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

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

doi:10.1016/j.freeradbiomed.2023.01.026

Cited by 17 publications

(14 citation statements)

References 69 publications

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“…The NOX downregulation can suppress oxidative stress, thereby improving pancreatic β-cells insulin secretion and reducing β-cells apoptosis [ 160 ]. Increased NOX4 expression promotes ferroptosis in OBs [ 21 ]. In an HG environment, the NFκB pathway promotes NOX4 expression, activates RANKL, induces excessive TfR1 expression, and significantly reduces iron levels, which can lead to ferroptosis in OBs and promote OCs differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…This promotes the expression of NOX4, resulting in increased ROS production when NADPH is used as a substrate. Accumulation of lipid peroxides causes mitochondrial dysfunction and promotes iron-dependent cell death in OBs [ 21 ].…”

Section: Ferroptosis In Opmentioning

confidence: 99%

“…The expression of NOX4 is negatively regulated by several antioxidant factors [ 171 ]. Elevated levels of NOX4 result in the production of ROS and accumulation of lipid peroxidation, leading to morphological and functional impairments in OBs mitochondria and promoting ferroptosis in OBs [ 21 ]. Activating Transcription Factor 3 (ATF3), a member of the ATF/Cyclic AMP Response Element-Binding protein (CREB) transcription factor family, plays a crucial role in transcriptional repression and promotion with a dual function of regulating cell apoptosis, proliferation, and the cell cycle.…”

Section: Ferroptosis In T2dopmentioning

confidence: 99%

“…Disturbances in iron metabolism, including iron deficiency and overload, are also strongly associated with OP [ 19 , 20 ]. Excessive iron accumulation mediated by NADPH oxidase 4 (NOX4) can cause iron metabolism in osteoblasts (OBs), leading to OP [ 21 ]. DOP progression is accompanied by impaired glucolipid homeostasis and elevated plasma glucolipid metabolites; hence, ferroptosis may play a vital role in DOP pathogenesis [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Type 2 diabetic mellitus related osteoporosis: focusing on ferroptosis

Chen,

Zhao,

et al. 2024

J Transl Med

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With the aging global population, type 2 diabetes mellitus (T2DM) and osteoporosis(OP) are becoming increasingly prevalent. Diabetic osteoporosis (DOP) is a metabolic bone disorder characterized by abnormal bone tissue structure and reduced bone strength in patients with diabetes. Studies have revealed a close association among diabetes, increased fracture risk, and disturbances in iron metabolism. This review explores the concept of ferroptosis, a non-apoptotic cell death process dependent on intracellular iron, focusing on its role in DOP. Iron-dependent lipid peroxidation, particularly impacting pancreatic β-cells, osteoblasts (OBs) and osteoclasts (OCs), contributes to DOP. The intricate interplay between iron dysregulation, which comprises deficiency and overload, and DOP has been discussed, emphasizing how excessive iron accumulation triggers ferroptosis in DOP. This concise overview highlights the need to understand the complex relationship between T2DM and OP, particularly ferroptosis. This review aimed to elucidate the pathogenesis of ferroptosis in DOP and provide a prospective for future research targeting interventions in the field of ferroptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Ferroptosis In Opmentioning

confidence: 99%

Section: Ferroptosis In T2dopmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Type 2 diabetic mellitus related osteoporosis: focusing on ferroptosis

Chen,

Zhao,

et al. 2024

J Transl Med

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“…Studies have found that excessive iron accumulation is a risk factor for osteopenia and osteoporosis. Osteoporotic bone loss caused by excessive iron accumulation is driven by osteoblast ferroptosis triggered by NOX4 (NADPH oxidase 4) [ 37 ]. Hepcidin Antimicrobial Peptide ( HAMP ) is an iron homeostasis regulator.…”

Section: Discussionmentioning

confidence: 99%

Identification of osteoporosis ferroptosis-related markers and potential therapeutic compounds based on bioinformatics methods and molecular docking technology

Long,

Li,

et al. 2024

BMC Med Genomics

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Research background and purpose Osteoporosis (OP) is one of the most common bone diseases worldwide, characterized by low bone mineral density and susceptibility to pathological fractures, especially in postmenopausal women and elderly men. Ferroptosis is one of the newly discovered forms of cell death regulated by genes in recent years. Many studies have shown that ferroptosis is closely related to many diseases. However, there are few studies on ferroptosis in osteoporosis, and the mechanism of ferroptosis in osteoporosis is still unclear. This study aims to identify biomarkers related to osteoporosis ferroptosis from the GEO (Gene Expression Omnibus) database through bioinformatics technology, and to mine potential therapeutic small molecule compounds through molecular docking technology, trying to provide a basis for the diagnosis and treatment of osteoporosis in the future. Materials and methods We downloaded the ferroptosis-related gene set from the FerrDb database (http://www.zhounan.org/ferrdb/index.html), downloaded the data sets GSE56815 and GSE7429 from the GEO database, and used the R software “limma” package to screen differentially expressed genes (DEGs) from GSE56815, and intersected with the ferroptosis gene set to obtain ferroptosis-related DEGs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed by the R software “clusterProfiler” package. The random forest model was further screened to obtain essential ferroptosis genes. R software “corrplot” package was used for correlation analysis of essential ferroptosis genes, and the Wilcox test was used for significance analysis. The lncRNA-miRNA-mRNA-TF regulatory network was constructed using Cytoscape software. The least absolute shrinkage and selection operator (LASSO) was used to construct a disease diagnosis model, and a Receiver operating characteristic (ROC) curve was drawn to evaluate the diagnostic performance, and then GSE7429 was used to verify the reliability of the diagnosis model. Molecular docking technology was used to screen potential small molecule compounds from the Drugbank database. Finally, a rat osteoporosis model was constructed, and peripheral blood mononuclear cells were extracted for qRT-PCR detection to verify the mRNA expression levels of crucial ferroptosis genes. Result Six DEGs related to ferroptosis were initially screened out. GO function and KEGG pathway enrichment analysis showed that ferroptosis-related DEGs were mainly enriched in signaling pathways such as maintenance of iron ion homeostasis, copper ion binding function, and ferroptosis. The random forest model identified five key ferroptosis genes, including CP, FLT3, HAMP, HMOX1, and SLC2A3. Gene correlation analysis found a relatively low correlation between these five key ferroptosis genes. The lncRNA-miRNA-mRNA-TF regulatory network shows that BAZ1B and STAT3 may also be potential molecules. The ROC curve of the disease diagnosis model shows that the model has a good diagnostic performance. Molecular docking technology screened out three small molecule compounds, including NADH, Midostaurin, and Nintedanib small molecule compounds. qRT-PCR detection confirmed the differential expression of CP, FLT3, HAMP, HMOX1 and SLC2A3 between OP and normal control group. Conclusion This study identified five key ferroptosis genes (CP, FLT3, HAMP, HMOX1, and SLC2A3), they were most likely related to OP ferroptosis. In addition, we found that the small molecule compounds of NADH, Midostaurin, and Nintedanib had good docking scores with these five key ferroptosis genes. These findings may provide new clues for the early diagnosis and treatment of osteoporosis in the future.

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Role of Iron Accumulation in Osteoporosis and the Underlying Mechanisms

Gao

Weinberg

et al. 2023

CURR MED SCI

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

Cited by 17 publications

References 69 publications

Type 2 diabetic mellitus related osteoporosis: focusing on ferroptosis

Type 2 diabetic mellitus related osteoporosis: focusing on ferroptosis

Identification of osteoporosis ferroptosis-related markers and potential therapeutic compounds based on bioinformatics methods and molecular docking technology

Role of Iron Accumulation in Osteoporosis and the Underlying Mechanisms

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