组蛋白去乙酰化酶抑制剂对骨关节炎中Notch-NFAT信号通路调控的机制研究

Notch and Nuclear factor of activated T cells (NFAT) signaling pathways were both associated with osteoarthritis (OA), however, there is little known about the correlation between Notch and NFAT signaling pathway in OA. Previous studies showed that histone deacetylase inhibitor (HDACi) can affect the activities of Notch signaling pathway. Our previous studies showed that: Notch signaling pathway can affect the activities of NFAT; HDACi can regulate the activities of Notch signaling pathway in human chondrocytes; HDACi exerts protective effects on articular cartilage in OA. In the present study, we take clinical specimens, human chondrocytes and animal OA model as object to further investigate the mechanism of NFAT signaling pathway regulation by Notch signaling pathway and the regulatory effects on Notch-NFAT signaling pathway by HDACi in OA. Signaling pathway inhibitor or RNA interference as well as gene transfection were used in the present study. Our study will further reveal the pathogenesis of OA, and provide new ideas for exploring diseases modifying drugs for OA.

Notch和T细胞活化核因子（Nuclear factor of activated T cells, NFAT）信号通路与骨关节炎（Osteoarthritis, OA）关系密切，但是两者在OA中的联系尚无报道。既往研究表明：组蛋白去乙酰化酶抑制剂（Histone deacetylase inhibitor HDACi）可影响Notch信号通路的活性。我们的前期研究发现:Notch信号通路可影响人软骨细胞中NFAT信号通路的活性；HDACi可影响Notch信号通路的活性；HDACi 对OA中的关节软骨有保护作用。本课题以临床标本、人软骨细胞和动物OA模型为研究对象，应用信号通路抑制剂或RNA干扰、基因转染等方法进一步研究OA中Notch对NFAT信号通路的调控机制，并观察HDACi对Notch-NFAT信号通路的调控。本课题将进一步揭示OA的发病机制，为探索OA病情改善药物提供新的思路。

Notch和T细胞活化核因子（Nuclear factor of activated T cells, NFAT）信号通路与骨关节炎（Osteoarthritis, OA）关系密切。本项目初步研究了Notch信号通路在OA中作用及其与NFAT通路的关系，同时在动物实验中研究了TSA对Notch信号通路的影响。我们的结果表明：1.Notch和NFAT通路在OA中的表达明显异常；2.Notch信号通路可能涉及了OA的发病，抑制Notch信号通路可能对软骨细胞有一定的保护作用；3.Notch通路可调控软骨细胞中NFAT通路的表达；4.动物实验的研究表明：组蛋白去乙酰化酶抑制剂TSA可以通过调控Notch 信号通路的活性而发挥其对关节软骨的保护作用。