Suppression of YAP Ameliorates Cartilage Degeneration in Ankle Osteoarthritis via Modulation of the Wnt/β-Catenin Signaling Pathway.

IF 3.3 3区 医学 Q2 ENDOCRINOLOGY & METABOLISM
Calcified Tissue International Pub Date : 2024-09-01 Epub Date: 2024-07-02 DOI:10.1007/s00223-024-01242-z
Zhengrui Fan, Xingwen Zhao, Jianxiong Ma, Hongqi Zhan, Xinlong Ma
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Abstract

Ankle osteoarthritis is a relatively understudied condition and the molecular mechanisms involved in its development are not well understood. This investigation aimed to explore the role and underlying molecular mechanisms of Yes-associated protein (YAP) in rat ankle osteoarthritis. The results demonstrated that YAP expression levels were abnormally increased in the ankle osteoarthritis cartilage model. In addition, knockdown of YAP expression was shown to hinder the imbalance in ECM metabolism induced by IL-1β in chondrocytes, as demonstrated by the regulation of matrix metalloproteinase (MMP)-3, MMP-9, and MMP-13, a disintegrin, metalloprotease with thrombospondin motifs, aggrecan, and collagen II expression. Additional studies revealed that downregulation of YAP expression markedly inhibited the overexpression of β-catenin stimulated by IL-1β. Furthermore, inhibition of the Wnt/β-catenin signaling pathway reversed the ECM metabolism imbalance caused by YAP overexpression in chondrocytes. It is important to note that the YAP-specific inhibitor verteporfin (VP) significantly delayed the progression of ankle osteoarthritis. In conclusion, the findings highlighted the crucial role of YAP as a regulator in modulating the progression of ankle osteoarthritis via the Wnt/β-catenin signaling pathway. These findings suggest that pharmacological inhibition of YAP can be an effective and critical therapeutic target for alleviating ankle osteoarthritis.

Abstract Image

抑制 YAP 可通过调节 Wnt/β-Catenin 信号通路改善踝关节骨关节炎的软骨退化。
踝关节骨关节炎是一种研究相对较少的疾病,其发病的分子机制也不甚明了。本研究旨在探讨Yes相关蛋白(YAP)在大鼠踝关节骨关节炎中的作用及其分子机制。结果表明,YAP在踝关节骨关节炎软骨模型中的表达水平异常升高。此外,敲除 YAP 的表达还能阻止 IL-1β 在软骨细胞中诱导的 ECM 代谢失衡,具体表现为基质金属蛋白酶(MMP)-3、MMP-9 和 MMP-13、一种具有血栓软骨素基序的崩解蛋白、金属蛋白酶、凝集素和胶原蛋白 II 表达的调节。其他研究表明,下调 YAP 的表达可明显抑制 IL-1β 刺激的β-catenin 的过度表达。此外,抑制 Wnt/β-catenin 信号通路可逆转软骨细胞中因 YAP 过表达而导致的 ECM 代谢失衡。值得注意的是,YAP特异性抑制剂verteporfin(VP)能显著延缓踝关节骨关节炎的进展。总之,研究结果凸显了 YAP 在通过 Wnt/β-catenin 信号通路调节踝关节骨关节炎进展中的关键作用。这些研究结果表明,药理抑制 YAP 可以成为缓解踝关节骨关节炎的有效而关键的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Calcified Tissue International
Calcified Tissue International 医学-内分泌学与代谢
CiteScore
8.00
自引率
2.40%
发文量
112
审稿时长
4-8 weeks
期刊介绍: Calcified Tissue International and Musculoskeletal Research publishes original research and reviews concerning the structure and function of bone, and other musculoskeletal tissues in living organisms and clinical studies of musculoskeletal disease. It includes studies of cell biology, molecular biology, intracellular signalling, and physiology, as well as research into the hormones, cytokines and other mediators that influence the musculoskeletal system. The journal also publishes clinical studies of relevance to bone disease, mineral metabolism, muscle function, and musculoskeletal interactions.
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