Mechanical overloading induces GPX4-regulated chondrocyte ferroptosis in osteoarthritis via Piezo1 channel facilitated calcium influx

Wang, Shaoyi; Li, Weiwei; Zhang, Pengfei; Wang, Zihao; Ma, Xiaoyuan; Liu, Chuanju; Vasilev, Krasimir; Zhang, Lei; Zhou, Xiao-cong; Liu, Liang; Hayball, John D.; Dong, Shuli; Li, Yuhua; Gao, Yuan; Cheng, Lei; Zhao, Yunpeng

doi:10.1016/j.jare.2022.01.004

Cited by 92 publications

(63 citation statements)

References 51 publications

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“…As GPX-4 acts as a gatekeeper against ferroptosis, it is suppressed in ferroptosis and often used as a marker for its evaluation. When subjected to mechanical loading concentrated in knee joints by destabilizing the medial meniscus, chondrocyte-specific Gpx-4 knockout mice developed more severe osteoarthritis compared with their wild-type littermates ( 48 ). Mechanical loading on human cartilage and mouse chondrocytes increased Piezo1 expression and triggered GPX-4-mediated ferroptosis, which was attenuated upon the suppression of Piezo1 activity using GsMTx4, a selective inhibitor of cationic MS channels, or preventing extracellular Ca 2+ influx, thereby eventually reducing the severity of osteoarthritis.…”

Section: The Role Of Piezo1 In Ferroptosismentioning

confidence: 99%

Mechanosensitive ion channels in apoptosis and ferroptosis: focusing on the role of Piezo1

Kim

Hyun

2023

BMB Rep

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Mechanosensitive ion channels sense mechanical stimuli applied directly to the cellular membranes or indirectly through their tethered components, provoking cellular mechanoresponses. Among others, Piezo1 mechanosensitive ion channel is a relatively novel Ca 2+ -permeable channel that is primarily present in non-sensory tissues. Recent studies have demonstrated that Piezo1 plays an important role in Ca 2+ -dependent cell death, including apoptosis and ferroptosis, in the presence of mechanical stimuli. It has also been proven that cancer cells are sensitive to mechanical stresses due to higher expression levels of Piezo1 compared to normal cells. In this review, we discuss Piezo1-mediated cell death mechanisms and therapeutic strategies to inhibit or induce cell death by modulating the activity of Piezo1 with pharmacological drugs or mechanical perturbations induced by stretch and ultrasound.

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Section: The Role Of Piezo1 In Ferroptosismentioning

confidence: 99%

Mechanosensitive ion channels in apoptosis and ferroptosis: focusing on the role of Piezo1

Kim

Hyun

2023

BMB Rep

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“…This is illustrated by the paucity of effective treatments for lysosomal disorders [279]. In addition, ferroptotic pores enhance lipid peroxidation by Ca2+ influx, further lowering GPX4 concentrations [280,281]. Therefore, once activated, ferroptotic cell death takes on a life of its own by initiating a vicious circle of body fat "rusting" and cell death [282].…”

Section: Membrane Lipid Replacement (Mlr)mentioning

confidence: 99%

Long COVID and the Neuroendocrinology of Microbial Translocation Outside the GI Tract: Some Treatment Strategies

Sfera

Osorio

Hazan³

et al. 2022

Endocrines

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Similar to previous pandemics, COVID-19 has been succeeded by well-documented post-infectious sequelae, including chronic fatigue, cough, shortness of breath, myalgia, and concentration difficulties, which may last 5 to 12 weeks or longer after the acute phase of illness. Both the psychological stress of SARS-CoV-2 infection and being diagnosed with COVID-19 can upregulate cortisol, a stress hormone that disrupts the efferocytosis effectors, macrophages, and natural killer cells, leading to the excessive accumulation of senescent cells and disruption of biological barriers. This has been well-established in cancer patients who often experience unrelenting fatigue as well as gut and blood–brain barrier dysfunction upon treatment with senescence-inducing radiation or chemotherapy. In our previous research from 2020 and 2021, we linked COVID-19 to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) via angiotensin II upregulation, premature endothelial senescence, intestinal barrier dysfunction, and microbial translocation from the gastrointestinal tract into the systemic circulation. In 2021 and 2022, these hypotheses were validated and SARS-CoV-2-induced cellular senescence as well as microbial translocation were documented in both acute SARS-CoV-2 infection, long COVID, and ME/CFS, connecting intestinal barrier dysfunction to disabling fatigue and specific infectious events. The purpose of this narrative review is to summarize what is currently known about host immune responses to translocated gut microbes and how these responses relate to fatiguing illnesses, including long COVID. To accomplish this goal, we examine the role of intestinal and blood–brain barriers in long COVID and other illnesses typified by chronic fatigue, with a special emphasis on commensal microbes functioning as viral reservoirs. Furthermore, we discuss the role of SARS-CoV-2/Mycoplasma coinfection in dysfunctional efferocytosis, emphasizing some potential novel treatment strategies, including the use of senotherapeutic drugs, HMGB1 inhibitors, Toll-like receptor 4 (TLR4) blockers, and membrane lipid replacement.

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“…Recent research has shown that chondrocyte ferroptosis plays a role in the pathogenesis of OA. Mechanical overloading may aggravate OA by causing glutathione peroxidase 4 (GPX4)-related ferroptosis [9]. GPX4 was found at the crossroads of two processes that regulate OA progression: ferroptosis and extracellular matrix degradation [10].…”

Section: Introductionmentioning

confidence: 99%

Exploring the mechanisms of age-related osteoarthritis associated with ferroptosis and autophagy using transcriptomics-based integrated analysis

Yan

Yin

Qin

et al. 2023

Preprint

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Ferroptosis and autophagy, parts of regulated cell death, are essential in osteoarthritis, however, their mechanisms in age-related osteoarthritis (OA) are unclear. This study aims to investigate age-related OA cartilage hub genes associated with ferroptosis and autophagy and predict interaction mechanisms. We used GEO2R to identify age-related differentially expressed genes (DEGs) in GSE66554. We intersected DEGs with data from Ferroptosis and Autophagy Database to obtain ferroptosis and autophagy DEGs. We performed differential expression analysis, enrichment analysis, and hub gene screening. After validation of hub genes in GSE33754 with expression patterns analysis, we identified and verified three key hub genes utilising heatmaps, correlation analysis, receiver operator characteristic (ROC) analysis and quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and predicted their interaction mechanisms. We found 27 ferroptosis DEGs and 29 autophagy DEGs associated with cartilage ageing. Enrichment analysis revealed autophagy-related terms. After validation, three key hub genes, lysosomal-associated membrane protein 2 (Lamp2), NRAS proto-oncogene (Nras), and activating transcription factor 6 (Atf6) were identified. ROC analysis demonstrated that their independent and combined use in diagnosing cartilage ageing was accurate. Their expression was found to be consistent with bioinformatic analysis by qRT-PCR. Protein-RNA interaction, transcription factor-DNA interaction, competing endogenous RNA, and protein-protein interaction was predicted, revealing that key hub genes are essential in cartilage ageing. Using bioinformatics and experiments, we identified three key hub genes, Lamp2, Nras, and Atf6, associated with ferroptosis and autophagy in aged cartilage. These findings may help us understand cartilage ageing and treat age-related osteoarthritis.

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Mechanical overloading induces GPX4-regulated chondrocyte ferroptosis in osteoarthritis via Piezo1 channel facilitated calcium influx

Cited by 92 publications

References 51 publications

Mechanosensitive ion channels in apoptosis and ferroptosis: focusing on the role of Piezo1

Mechanosensitive ion channels in apoptosis and ferroptosis: focusing on the role of Piezo1

Long COVID and the Neuroendocrinology of Microbial Translocation Outside the GI Tract: Some Treatment Strategies

Exploring the mechanisms of age-related osteoarthritis associated with ferroptosis and autophagy using transcriptomics-based integrated analysis

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