ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1577234
This article is part of the Research TopicAdvancing Cartilage Regeneration and Repair: Biomaterials and Biomechanical StrategiesView all articles
Thrombospondin-1 Mitigates Osteoarthritis Progression by Inhibiting Mechanical stress-induced Chondrocyte Ferroptosis via the Integrin/YAP Pathway
Provisionally accepted
- 1Shandong University, Jinan, China
- 2Shandong Provincial Qianfoshan Hospital, Jinan, Shandong Province, China
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Word Count:221) Osteoarthritis in weight-bearing joints significantly impacts the quality of life in middle-aged and elderly individuals. Abnormal mechanical stress can induce chondrocytes ferroptosis, thereby accelerating the progression of osteoarthritis. In this study, we investigated the therapeutic effects of targeting chondrocyte ferroptosis to delay the progression of osteoarthritis and identified a potential therapeutic target. Through transcriptomic sequencing analysis, we identified a potential association between thrombospondin-1 (THBS1) and mechanical stress-induced chondrocyte ferroptosis. We used via adeno-associated virus-mediated THBS1 overexpression, cell pressurization model and GPX4-conditional knockout (Col2a1-CreERT: GPX4 flox/flox ) mice to verify the regulatory effect of THBS1 on chondrocytes ferroptosis. Additionally, protein interaction network analysis, immunofluorescence co-localization, and coimmunoprecipitation were conducted to investigate the mechanism by which THBS1 modulates chondrocytes ferroptosis. The expression of THBS1 protein was reduced in load-bearing cartilage tissue in humans. THBS1 suppressed chondrocytes ferroptosis induced by excessive mechanical stress. Immunofluorescence co-localization and CO-IP experiments indicated that integrin αV/β1 serves as the membrane receptor through which THBS1 regulates chondrocyte ferroptosis under mechanical stress. Upon activation, integrin αV/β1 modulated YAP1 nuclear translocation, thereby affecting GPX4 activity. Intra-articular injection of THBS1 synthetic peptides effectively reduced cartilage damage in mouse OA models, protecting articular cartilage and slowing the progression of osteoarthritis. Our results indicate THBS1 regulates mechanical stress-induced chondrocyte ferroptosis through the Integrin/YAP pathway. Furthermore, THBS1 effectively slows the progression of osteoarthritis and protects articular cartilage.
Keywords: Osteoarthritis, ferroptosis, Mechanical Stress, THBS1, Chondrocytes
Received: 15 Feb 2025; Accepted: 28 Apr 2025.
Copyright: © 2025 Wang, Zhou, Zhang, Zhai, Zhang and Guo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Shaoyi Wang, Shandong University, Jinan, China
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