Oxidative Stress and Inflammation in Osteoporosis: Molecular Mechanisms Involved and the Relationship with microRNAs

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(4), P. 3772 - 3772

Published: Feb. 14, 2023

Osteoporosis is characterized by the alteration of bone homeostasis due to an imbalance between osteoclastic resorption and osteoblastic formation. Estrogen deficiency causes loss postmenopausal osteoporosis, pathogenesis which also involves oxidative stress, inflammatory processes, dysregulation expression microRNAs (miRNAs) that control gene at post-transcriptional levels. Oxidative increase in reactive oxygen species (ROS), proinflammatory mediators altered levels miRNAs enhance osteoclastogenesis reduce osteoblastogenesis through mechanisms involving activation MAPK transcription factors. The present review summarizes principal molecular involved role ROS cytokines on osteoporosis. Moreover, it highlights interplay among miRNA levels, state. In fact, ROS, activating transcriptional factors, can affect expression, regulate production processes. Therefore, should help identifying targets for development new therapeutic approaches osteoporotic treatment improve quality life patients.

Language: Английский

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Type 2 diabetic mellitus related osteoporosis: focusing on ferroptosis

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: April 30, 2024

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

Language: Английский

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Interaction between ferroptosis and TNF‐α: Impact in obesity‐related osteoporosis

The FASEB Journal, Journal Year: 2023, Volume and Issue: 37(6)

Published: May 18, 2023

Abstract The relationship of obesity and osteoporosis has been widely studied over the past years. However, implications for bone health remain controversial, underlying molecular mechanism is not yet fully understood. This study demonstrated that high‐fat diet‐induced leads to significantly decreased volume/tissue volume (BV/TV), trabecular number (Tb.N), cortical thickness (Ct.Th) male rat femur after mechanical loading effects body weight were controlled. HFD‐induced obese rats exhibited attenuated expression ferroptosis inhibitory protein SLC7A11 GPX4 in tissues, which was correlated with elevated serum TNF‐α concentration. Ferroptosis inhibitor administration could effectively rescue osteogenesis‐associated type H vessels osteoprogenitors, downregulate levels ameliorate loss rats. Since both affect vessel formation, we further investigated interaction between TNF‐α, its impact osteogenesis angiogenesis vitro. In human osteoblast‐like MG63 umbilical vein endothelial cells (HUVEC), TNF‐α/TNFR2 signaling promoted cystine uptake GSH biosynthesis provide protection against low‐dose inducer erastin. While, TNF‐α/TNFR1 facilitated presence high‐dose erastin through ROS accumulation. Moreover, regulated ferroptosis‐induced osteogenic angiogenic dysfunctions based on regulatory role. Meanwhile, inhibitors reduce intracellular overproduction enhance TNF‐α‐treated HUVECs. revealed angiogenesis, provides new insights into pathogenesis regenerative therapy obesity‐related osteoporosis.

Language: Английский

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Eldecalcitol protected osteocytes against ferroptosis of D-gal-induced senescent MLO-Y4 cells and ovariectomized mice

Experimental Gerontology, Journal Year: 2024, Volume and Issue: 189, P. 112408 - 112408

Published: March 23, 2024

Active vitamin D analog eldecalcitol is clinically applied in treatment of postmenopausal osteoporosis. This study aims to determine the role protection osteocytes from senescence and associated ferroptosis. The MLO-Y4 were exposed D-gal inducing senescence. ovariectomized (OVX) mice treated with using as an aging inducer intraperitoneally injected eldecalcitol. multiplexed confocal imaging, fluorescence situ hybridization transmission electron microscopy assessing osteocytic properties. Immunochemical staining immunoblotting carried out detect abundance expression molecules. ablation receptor led a reduction amounts osteocytes, loss dendrites, increase mRNA SASP factors protein senescent factors, well changes ferroptosis-related genes (PTGS2 & RGS4). Eldecalcitol reversed phenotypes cells shown by improving cell morphology density, decreasing β-gal-positive accumulation, down-regulating (P16, P21 P53). reduced intracellular ROS MDA productions, elevated JC-1 aggregates, up-regulated Nrf2 GPX4. exhibited osteopreserve effects D-gal-induced OVX mice. imaging displayed its improvement on network organization. decreased numbers at tibial diaphysis SADS assay attenuated down-regulated senescence-related restored levels ferroptotic biomarkers osteocytes-enriched bone fraction. It 4-HNE area, stimulated Nrf2-positive staining, promoted nuclear translocation inhibited Nrf2, respectively, present revealed ameliorative ferroptosis contributing preservation against osteoporosis

Language: Английский

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An update on the role of ferroptosis in the pathogenesis of osteoporosis

EFORT Open Reviews, Journal Year: 2024, Volume and Issue: 9(8), P. 712 - 722

Published: Aug. 1, 2024

Ferroptosis is a novel form of programmed cell death, distinguished from apoptosis, autophagy, and necrosis has received much attention since it was defined in 2012. Ferroptotic cells physiologically exhibit iron metabolism dysregulation, oxidative stress, lipid peroxidation. Morphologically, they show plasma membrane disruption, cytoplasmic swelling, mitochondrial condensation. Osteoporosis taken more seriously as the proportion aging population continues to increase globally. Interestingly, ferroptosis been demonstrated be involved development progression osteoporosis many extant studies. The review summarizes metabolism, peroxidation, different regulatory signals ferroptosis. Changes signaling mechanisms within osteoblasts, osteoclasts, osteocytes after occur are explained here. Studies showed play an important role models (diabetes osteoporosis, postmenopausal glucocorticoid-induced osteoporosis). Inhibitors EC (Exos) targeting could ameliorate bone loss osteoporotic mice by protecting against Shortly, we hope that effective appropriate clinical therapy means will utilized treatment osteoporosis.

Language: Английский

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Aucubin Promotes BMSCs Proliferation and Differentiation of Postmenopausal Osteoporosis Patients by Regulating Ferroptosis and BMP2 Signalling

Journal of Cellular and Molecular Medicine, Journal Year: 2025, Volume and Issue: 29(2)

Published: Jan. 1, 2025

Postmenopausal osteoporosis (PMOP) is a chronic systemic bone metabolism disorder. Promotion in the patterns of human marrow mesenchymal stem cells (hBMSCs) differentiation towards osteoblasts contributes to alleviating osteoporosis. Aucubin, natural compound isolated from well-known herbal medicine Eucommia, was previously shown possess various pharmacological effects. However, its effects on hBMSCs PMOP patients are unknown. The aim this present research investigate impact and underlying process aucubin cell proliferation osteogenic patients. ability inhibit ferroptosis induced by erastin detected; ROS production, ferrous ion levels, SOD, MDA, GPX activities were tested using commercial kits. Next, ALP staining, ARS RT-qPCR, RNA-sequencing, Western blot applied for determining mRNA protein expression levels associated with osteogenesis hBMSCs. study also explored involvement BMP2/Smads signalling promoting evaluated intervention an ovariectomised rat model. results indicated that significantly inhibited generation oxidative stress protected against Additionally, facilitated activating BMP2/SMADs pathway attenuated progression OVX rats, suggesting potential therapeutic benefit postmenopausal (PMOP).

Language: Английский

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Regulation of enzymatic lipid peroxidation in osteoblasts protects against postmenopausal osteoporosis

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 17, 2025

Oxidative stress plays a critical role in postmenopausal osteoporosis, yet its impact on osteoblasts remains underexplored, limiting therapeutic advances. Our study identifies phospholipid peroxidation as key feature of osteoporosis. Estrogen regulates the transcription glutathione peroxidase 4 (GPX4), an enzyme crucial for reducing peroxides osteoblasts. The deficiency estrogen reduces GPX4 expression and increases Inhibition or knockout impairs osteoblastogenesis, while elimination rescues bone formation mitigates Mechanistically, 4-hydroxynonenal, end-product peroxidation, binds to integrin-linked kinase triggers protein degradation, disrupting RUNX2 signaling inhibiting osteoblastogenesis. Importantly, we identified two natural allosteric activators GPX4, 6- 8-Gingerols, which promote osteoblastogenesis demonstrate anti-osteoporotic effects. findings highlight detrimental underscore promising target osteoporosis treatment.

Language: Английский

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Identification of ferroptosis-associated biomarkers for the potential diagnosis and treatment of postmenopausal osteoporosis

Frontiers in Endocrinology, Journal Year: 2022, Volume and Issue: 13

Published: Aug. 29, 2022

Objective Postmenopausal osteoporosis (PMOP) is one of the most commonly occurring conditions worldwide and characterized by estrogen deficiency as well persistent calcium loss with age. The aim our study was to identify significant ferroptosis-associated biomarkers for PMOP. Methods materials We obtained training dataset from Gene Expression Omnibus (GEO) database using GSE56815 expression profiling data. Meanwhile, we extracted genes further analysis. Differentially expressed (DEFAGs) between OP patients normal controls were selected “limma” package. established a gene signature models, specifically, random forest (RF) support vector machine (SVM) models. It validated in another (GSE56814) which also showed high AUC: 0.98, indicating diagnostic value. Using consensus clustering, patient subtypes identified. A ferroptosis associated (FAG)-Scoring scheme developed PCA. important candidate compared different ferrclusters geneclusters. Results There DEFAGs acquired, five (HMOX1, HAMP, LPIN1, MAP3K5, FLT3) establishing signature. Analyzed ROC curve, RF model had higher AUC value than SVM (RF AUC:1.00). Considering these results, chosen be appropriate model. Later, based on levels DEFAGs, clinical application nomogram established. divided into two (ferrcluster A, B genecluster B, respectively) according clustering method differentially (DEGs). Ferrcluster score ferrcluster respectively. COL1A1 significantly gencluster respectively, while there no statistical difference term VDR gene, COL1A2 genes, PTH expressions together B. Conclusions On basis explanatory variables MAP3K5 FLT3), identified differently categorized that may potentially applied early diagnosis individualized treatment ER IL-6 are OP, however, more studies still anticipated elucidate relationship OP.

Language: Английский

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Mitophagy—A New Target of Bone Disease

Biomolecules, Journal Year: 2022, Volume and Issue: 12(10), P. 1420 - 1420

Published: Oct. 4, 2022

Bone diseases are usually caused by abnormal metabolism and death of cells in bones, including osteoblasts, osteoclasts, osteocytes, chondrocytes, bone marrow mesenchymal stem cells. Mitochondrial dysfunction, as an important cause cell metabolism, is widely involved the occurrence progression multiple diseases, osteoarthritis, intervertebral disc degeneration, osteoporosis, osteosarcoma. As selective mitochondrial autophagy for damaged or dysfunctional mitochondria, mitophagy closely related to quality control homeostasis. Accumulating evidence suggests that plays regulatory role disease, indicating regulating level may be a new strategy bone-related diseases. Therefore, reviewing relevant literature recent years, this paper reviews potential mechanism osteosarcoma, provide theoretical basis research

Language: Английский

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Silymarin prevents iron overload induced bone loss by inhibiting oxidative stress in an ovariectomized animal model

Chemico-Biological Interactions, Journal Year: 2022, Volume and Issue: 366, P. 110168 - 110168

Published: Sept. 7, 2022

Language: Английский

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