Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan 430072, China.
Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430072, China.
Int J Mol Sci. 2023 Feb 16;24(4):4022. doi: 10.3390/ijms24044022.
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.
过度的机械压力是骨关节炎（OA）的突出危险因素，导致软骨破坏和退化。然而，OA 中导致机械信号转导的潜在分子机制尚不清楚。Piezo 型机械敏感离子通道成分 1（Piezo1）是一种钙通透性机械敏感离子通道，为细胞提供机械敏感性，但它在 OA 发展中的作用尚未确定。在此，我们发现 Piezo1 在 OA 软骨中表达上调，其激活导致软骨细胞凋亡。Piezo1 的敲低可保护软骨细胞免于凋亡，并在机械应变下维持分解代谢和合成代谢的平衡。在体内，Piezo1 抑制剂 Gsmtx4 显著改善 OA 的进展，抑制软骨细胞凋亡，并加速软骨基质的产生。在机制上，我们观察到在软骨细胞中机械应变下钙调神经磷酸酶（CaN）活性升高和激活 T 细胞核因子 1（NFAT1）核转位。CaN 或 NFAT1 的抑制剂可挽救软骨细胞中机械应变引起的病理变化。总的来说，我们的研究结果表明，Piezo1 是对机械信号的必需分子反应，并通过 CaN/NFAT1 信号通路调节软骨细胞中的凋亡和软骨基质代谢，而 Gsmtx4 可能是治疗 OA 的一种有吸引力的治疗药物。
