Gsmtx4 Alleviated Osteoarthritis through Piezo1/Calcineurin/NFAT1 Signaling Axis under Excessive Mechanical Strain.
Gsmtx4 Alleviated Osteoarthritis through Piezo1/Calcineurin/NFAT1 Signaling Axis under Excessive Mechanical Strain.
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Gsmtx4 通过 Piezo1/Calcineurin/NFAT1 信号轴在过度机械应变下减轻骨关节炎
DOI：
10.3390/ijms24044022
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发表时间：
2023-02-16
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
过度的机械应变是骨关节炎（OA）的主要危险因素，导致软骨破坏和退化。然而，在OA中，机械信号转导的潜在分子机制仍不清楚。压电型机械敏感性离子通道组分1（Piezo 1）是钙渗透性机械敏感性离子通道，并为细胞提供机械敏感性，但其在OA发展中的作用尚未确定。在此，我们发现Piezo 1在OA软骨中的表达上调，并且其激活有助于软骨细胞凋亡。敲低Piezo 1基因可以保护软骨细胞免于凋亡，并维持机械应力下的分解代谢和合成代谢平衡。在体内，Piezo 1抑制剂Gsmtx 4可明显改善OA的进展，抑制软骨细胞凋亡，促进软骨基质的生成。在机械应变下，我们观察到软骨细胞中钙调神经磷酸酶（CaN）的活性升高和活化T细胞核因子1（NFAT 1）的核转染。CaN或NFAT 1的抑制剂挽救了软骨细胞中由机械应变引起的病理变化。总之，我们的研究结果表明，Piezo 1是必不可少的分子响应机械信号，并通过CaN/NFAT 1信号轴在软骨细胞中调节细胞凋亡和软骨基质代谢，Gsmtx 4可能是一个有吸引力的治疗药物治疗OA。
Excessive mechanical strain is the prominent risk factor for osteoarthritis (OA), causing cartilage destruction and degeneration. However, the underlying molecular mechanism contributing to mechanical signaling transduction remains unclear in OA. Piezo type mechanosensitive ion channel component 1 (Piezo1) is a calcium-permeable mechanosensitive ion channel and provides mechanosensitivity to cells, but its role in OA development has not been determined. Herein, we found up-regulated expression of Piezo1 in OA cartilage, and that its activation contributes to chondrocyte apoptosis. The knockdown of Piezo1 could protect chondrocytes from apoptosis and maintain the catabolic and anabolic balance under mechanical strain. In vivo, Gsmtx4, a Piezo1 inhibitor, markedly ameliorated the progression of OA, inhibited the chondrocyte apoptosis, and accelerated the production of the cartilage matrix. Mechanistically, we observed the elevated activity of calcineurin (CaN) and the nuclear transfection of nuclear factor of activated T cells 1 (NFAT1) under mechanical strain in chondrocytes. Inhibitors of CaN or NFAT1 rescued the pathologic changes induced by mechanical strain in chondrocytes. Overall, our findings revealed that Piezo1 was the essential molecule response to mechanical signals and regulated apoptosis and cartilage matrix metabolism via the CaN/NFAT1 signaling axis in chondrocytes, and that Gsmtx4 could be an attractive therapeutic drug for OA treatment.
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影响因子：
5.6
作者：
Musumeci G;Castrogiovanni P;Trovato FM;Weinberg AM;Al-Wasiyah MK;Alqahtani MH;Mobasheri A
通讯作者：
Mobasheri A
影响因子：
16.6
作者：
Cox CD;Bae C;Ziegler L;Hartley S;Nikolova-Krstevski V;Rohde PR;Ng CA;Sachs F;Gottlieb PA;Martinac B
通讯作者：
Martinac B
影响因子：
7
作者：
He, B. H.;Christin, M.;Sharif-Naeini, R.
通讯作者：
Sharif-Naeini, R.
影响因子：
3.3
作者：
Ikeda R;Arimura D;Saito M
通讯作者：
Saito M
影响因子：
5.5
作者：
Behringer, Erik J.;Segal, Steven S.
通讯作者：
Segal, Steven S.