Mechanosignalling in cartilage: an emerging target for the treatment of osteoarthritis

Nature Reviews Rheumatology, Journal Year: 2021, Volume and Issue: 18(2), P. 67 - 84

Published: Dec. 21, 2021

Language: Английский

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

Journal of Advanced Research, Journal Year: 2022, Volume and Issue: 41, P. 63 - 75

Published: Jan. 11, 2022

Excessive mechanical stress is closely associated with cell death in various conditions. Exposure of chondrocytes to excessive loading leads a catabolic response as well exaggerated death. Ferroptosis recently identified form during aging and degeneration. However, it's potential association remains be illustrated.To identify whether can cause ferroptosis. To explore the role overloading chondrocyte ferroptosis.Chondrocytes were collected from unloading zones cartilage patients osteoarthritis (OA), ferroptosis phenotype was analyzed through transmission electron microscope microarray. Moreover, relationship between OA by GPX4-conditional knockout (Col2a1-CreERT: GPX4flox/flox) mice model cultured high strain stress. Furthermore, Piezo1 ion channel development explored using its inhibitor (GsMTx4) agonist (Yoda1). Additionally, calcium-free medium stress, tested.Human mouse experiments revealed that induce GPX4-associated Conditional GPX4 aggravated experimental process, while additional treatment suppressor protein (FSP-1) coenzyme Q10 (CoQ10) abated GPX4-CKO mice. In experiments, inhibition activity increased expression, attenuated reduced severity osteoarthritis. induced damage largely abolished blocking calcium influx medium.Our findings show induces activation subsequent chondrocytes, which might provide target for treatment.

Language: Английский

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Roles of mechanosensitive channel Piezo1/2 proteins in skeleton and other tissues

Bone Research, Journal Year: 2021, Volume and Issue: 9(1)

Published: Oct. 20, 2021

Mechanotransduction is a fundamental ability that allows living organisms to receive and respond physical signals from both the external internal environments. The mechanotransduction process requires range of special proteins termed mechanotransducers convert mechanical forces into biochemical in cells. Piezo are mechanically activated nonselective cation channels largest plasma membrane ion reported thus far. regulation two family members, Piezo1 Piezo2, has been have essential functions mechanosensation transduction different organs tissues. Recently, predominant contributions were occur skeletal system, especially bone development mechano-stimulated homeostasis. Here we review current studies focused on tissue-specific Piezo2 various backgrounds with highlights their importance regulating cell mechanotransduction. In this review, emphasize diverse related signaling pathways osteoblast lineage cells chondrocytes. We also summarize our understanding channel structures key findings about PIEZO gene mutations human diseases.

Language: Английский

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Piezo1 Channels as Force Sensors in Mechanical Force-Related Chronic Inflammation

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

Published: Jan. 26, 2022

Mechanical damage is one of the predisposing factors inflammation, and it runs through entire inflammatory pathological process. Repeated or persistent damaging mechanical irritation leads to chronic diseases. The mechanism how forces induce inflammation not fully understood. Piezo1 a newly discovered mechanically sensitive ion channel. channel opens in response stimuli, transducing signals into an cascade cell leading tissue inflammation. A large amount evidence shows that plays vital role occurrence progression This mini-review briefly presents new responds different stresses trigger various tissues. discovery provides insights for treatment diseases related stress. Inhibiting transduction can inhibit improve outcome at early stage. pharmacology has shown bright prospects. development tissue-specific drugs clinical use may be target treating

Language: Английский

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Self-amplifying loop of NF-κB and periostin initiated by PIEZO1 accelerates mechano-induced senescence of nucleus pulposus cells and intervertebral disc degeneration

Molecular Therapy, Journal Year: 2022, Volume and Issue: 30(10), P. 3241 - 3256

Published: May 26, 2022

Abnormal mechanical load is a main risk factor of intervertebral disc degeneration (IDD), and cellular senescence pathological change in IDD. In addition, extracellular matrix (ECM) stiffness promotes human nucleus pulposus cells (hNPCs) senescence. However, the molecular mechanism underlying mechano-induced IDD progression not yet fully elucidated. First, we demonstrated that mechano-stress promoted hNPCs via NF-κB signaling. Subsequently, identified periostin as mechano-responsive molecule through unbiased sequencing, which was transcriptionally upregulated by p65; moreover, secreted senescent further catabolic process activating NF-κB, forming positive loop. Both Postn (encoding periostin) knockdown siRNA inactivation neutralizing antibodies alleviated NPCs Furthermore, found initiated feedback PIEZO1. PIEZO1 activation Yoda1 induced severe rat tails without compression, Yoda1-induced vivo. Here, reported for first time self-amplifying loop under accelerated senescence, leading to antibodies, may serve potential therapeutic agents IDD, interrupted this

Language: Английский

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Osteoarthritis year in review 2022: biology

Osteoarthritis and Cartilage, Journal Year: 2022, Volume and Issue: 30(12), P. 1575 - 1582

Published: Sept. 20, 2022

Language: Английский

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Piezo2 expressing nociceptors mediate mechanical sensitization in experimental osteoarthritis

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: April 29, 2023

Non-opioid targets are needed for addressing osteoarthritis pain, which is mechanical in nature and associated with daily activities such as walking climbing stairs. Piezo2 has been implicated the development of but mechanisms by this occurs remain poorly understood, including role nociceptors. Here we show that nociceptor-specific conditional knock-out mice were protected from sensitization inflammatory joint pain female mice, male well both knee swelling repeated intra-articular injection nerve growth factor mice. Single cell RNA sequencing mouse lumbar dorsal root ganglia situ hybridization human revealed a subset nociceptors co-express Ntrk1 (the gene encodes receptor TrkA). These results suggest factor-mediated nociceptors, critical osteoarthritic also dependent on Piezo2, targeting may represent therapeutic option control.

Language: Английский

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Activation of Piezo1 promotes osteogenic differentiation of aortic valve interstitial cell through YAP-dependent glutaminolysis

Science Advances, Journal Year: 2023, Volume and Issue: 9(22)

Published: June 2, 2023

Hemodynamic overload and dysregulation of cellular metabolism are involved in development calcific aortic valve disease (CAVD). However, how mechanical stress relates to metabolic changes CAVD remains unclear. Here, we show that Piezo1, a mechanosensitive ion channel, regulated glutaminase 1 (GLS1)-mediated glutaminolysis promote osteogenic differentiation interstitial cells (VICs). In vivo, two models stenosis were constructed by ascending constriction (AAC) direct wire injury (DWI). Inhibition Piezo1 GLS1 these respectively mitigated lesion. vitro, activation induced Yoda1 oscillatory triggered responses VICs, which prevented inhibition or knockdown. Mechanistically, promoted calcium-dependent Yes-associated protein (YAP) activation. YAP modulated GLS1-mediated glutaminolysis, enhanced through histone acetylation runt-related transcription factor 2 (RUNX2) promoters. Together, our work provided cross-talk between mechanotransduction the context CAVD.

Language: Английский

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Unveiling inflammatory and prehypertrophic cell populations as key contributors to knee cartilage degeneration in osteoarthritis using multi-omics data integration

Annals of the Rheumatic Diseases, Journal Year: 2024, Volume and Issue: 83(7), P. 926 - 944

Published: Feb. 7, 2024

Objectives Single-cell and spatial transcriptomics analysis of human knee articular cartilage tissue to present a comprehensive transcriptome landscape osteoarthritis (OA)-critical cell populations. Methods RNA sequencing spatially resolved transcriptomic technology have been applied characterise the cellular heterogeneity which were collected from 8 OA donors, 3 non-OA control total 19 samples. The novel chondrocyte population marker genes interest validated by immunohistochemistry staining, quantitative real-time PCR, etc. OA-critical populations through integrative analyses publicly available bulk data large-scale genome-wide association studies. Results We identified 33 population-specific that define 11 populations, including 9 known 2 new is, pre-inflammatory (preInfC) inflammatory (InfC). findings make this an important addition literature include: (1) InfC activates mediator MIF-CD74; (2) prehypertrophic (preHTC) hypertrophic (HTC) are potentially populations; (3) most OA-associated differentially expressed reside in surface superficial zone; (4) prefibrocartilage (preFC) is major contributor stratification patients with OA, resulting both inflammatory-related subtype non-inflammatory-related subtype. Conclusions Our results highlight InfC, preHTC, preFC HTC as potential target for therapy. Also, we conclude profiling those might be used stratify patient defining cohorts clinical trials precision medicine.

Language: Английский

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Piezo Channels: Awesome Mechanosensitive Structures in Cellular Mechanotransduction and Their Role in Bone

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(12), P. 6429 - 6429

Published: June 16, 2021

Piezo channels are mechanosensitive ion located in the cell membrane and function as key cellular mechanotransducers for converting mechanical stimuli into electrochemical signals. Emerged molecular detectors of forces, channels’ functions bone have attracted more attention. Here, we summarize current knowledge review research advances by highlighting Piezo1′s role cells, including osteocyte, marrow mesenchymal stem (BM-MSC), osteoblast, osteoclast, chondrocyte. Moreover, diseases is summarized.

Language: Английский

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