Division of Rheumatology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Division of Rheumatology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Int Immunopharmacol. 2019 May;70:268-273. doi: 10.1016/j.intimp.2019.02.051. Epub 2019 Mar 6.
The TRPV2 cation channel has been recently implicated in the regulation of arthritis severity, joint damage, and in the invasive behavior of the fibroblast-like synoviocyte (FLS). However, its mechanism of action was unknown. In this study we characterize the cell signaling events mediating the TRPV2 suppressive activity in FLS invasiveness. Studies with FLS cell lines derived from patients with RA revealed that TRPV2-specific stimulation significantly reduced FLS adhesion to different extracellular matrices that shared binding to αν, β1 and β3 integrins. Localization of these integrins to the plasma membrane and numbers of thick and organized actin filaments were diminished by TRPV2 specific stimulation, and cells developed a round and non-polarized morphology. TRPV2 stimulation significantly reduced levels of activated RhoA, Rac1 and cofilin. RhoA activators were able to overcome the TRPV2-induced suppression on both RhoA activation and invasion. These new discoveries suggest that TRPV2 regulates key intracellular processes implicated in cell invasion in arthritis and other processes such as cancer, and has the potential to become a useful target for drug development.
瞬时受体电位香草酸亚型 2（TRPV2）阳离子通道最近被认为参与了关节炎严重程度、关节损伤以及成纤维样滑膜细胞（FLS）侵袭行为的调节。然而，其作用机制尚不清楚。在这项研究中，我们描述了介导 TRPV2 抑制 FLS 侵袭性的细胞信号事件。对源自 RA 患者的 FLS 细胞系的研究表明，TRPV2 特异性刺激显著降低了 FLS 对不同细胞外基质的黏附作用，这些细胞外基质与 αν、β1 和 β3 整联蛋白结合。这些整联蛋白在质膜上的定位和厚且组织化的肌动蛋白丝的数量减少，细胞呈现圆形且非极化形态。TRPV2 刺激显著降低了激活的 RhoA、Rac1 和丝切蛋白的水平。RhoA 激活剂能够克服 TRPV2 诱导的 RhoA 激活和侵袭抑制。这些新发现表明，TRPV2 调节关节炎和其他疾病（如癌症）中细胞侵袭所涉及的关键细胞内过程，具有成为药物开发有用靶点的潜力。
