TRPV4 activation induces TMJ degeneration via p38 MAPK/c-Fos/CXCLs axis

Degenerative joint disease mainly manifests abnormal bone and cartilage remodeling, articular disc deformation and synovial inflammation, and it is closely related to intraarticular overload. Activation of the mechanosensitive channel transient receptor potential vanilloid 4 (TRPV4) can lead to degeneration of the temporomandibular joint (TMJ) disc. However, the potential mechanism by which TRPV4 leads to TMJ degeneration are still unclear. The results showed that TRPV4 activation promoted upregulation of chemokines including CXCL6 and CXCL13 in disc cells, and such chemokine release facilitated the proliferation and migration of FLSs and aggravated the TMJ degeneration in rat. Mechanistically, TRPV4-induced p38 MAPK signaling pathway activation promoted chemokine expression via the nuclear translocation of p38 and c-Fos, thereby promoting the proliferation and migration by CXCL-CXCR interaction.退行性关节病（Degenerative joint disease）主要表现为骨与软骨异常重塑、关节盘变形及滑膜炎症，且与关节腔内负荷过载密切相关。机械敏感性离子通道瞬时受体电位香草酸亚型4（transient receptor potential vanilloid 4, TRPV4）的激活可诱导颞下颌关节（temporomandibular joint, TMJ）盘退变，但TRPV4介导颞下颌关节退变的潜在机制目前仍不明确。研究结果显示，TRPV4激活可促进关节盘细胞中CXCL6、CXCL13等趋化因子的表达上调；此类趋化因子的释放可促进成纤维样滑膜细胞（fibroblast-like synoviocytes, FLSs）的增殖与迁移，并加剧大鼠颞下颌关节的退变。从分子机制层面而言，TRPV4诱导的p38丝裂原活化蛋白激酶（p38 mitogen-activated protein kinase, p38 MAPK）信号通路激活，可通过p38与c-Fos的核转位促进趋化因子的表达，进而通过CXCL-CXCR相互作用介导细胞的增殖与迁移。