PDF(Pubmed)
Abstract：
Hyperplasia and migration of fibroblast-like synoviocytes (FLSs) are the key drivers in the pathogenesis of rheumatoid arthritis (RA) and joint destruction. Abundant Yes-associated protein (YAP), which is a powerful transcription co-activator for proliferative genes, was observed in the nucleus of inflammatory FLSs with unknown upstream mechanisms. Using Gene Expression Omnibus database analysis, it was found that Salvador homolog-1 (SAV1), the pivotal negative regulator of the Hippo-YAP pathway, was slightly downregulated in RA synovium. However, SAV1 protein expression is extremely reduced. Subsequently, it was revealed that SAV1 is phosphorylated, ubiquitinated, and degraded by interacting with an important serine-threonine kinase, G protein-coupled receptor (GPCR) kinase 2 (GRK2), which was predominately upregulated by GPCR activation induced by ligands such as prostaglandin E2 (PGE2) in RA. This process further contributes to the decreased phosphorylation, nuclear translocation, and transcriptional potency of YAP, and leads to aberrant FLSs proliferation. Genetic depletion of GRK2 or inhibition of GRK2 by paroxetine rescued SAV1 expression and restored YAP phosphorylation and finally inhibited RA FLSs proliferation and migration. Similarly, paroxetine treatment effectively reduced the abnormal proliferation of FLSs in a rat model of collagen-induced arthritis which was accompanied by a significant improvement in clinical manifestations. Collectively, these results elucidate the significance of GRK2 regulation of Hippo-YAP signaling in FLSs proliferation and migration and the potential application of GRK2 inhibition in the treatment of FLSs-driven joint destruction in RA.
摘要：
成纤维细胞样滑膜细胞（FLS）的增生和迁移是类风湿性关节炎（RA）和关节破坏发病的关键驱动因素。丰富的Yes相关蛋白（YAP），它是增殖基因的强大转录共激活因子，在具有未知上游机制的炎性FLS的核中观察到。使用基因表达综合数据库分析，发现萨尔瓦多同源物-1(SAV1)，Hippo-YAP通路的关键负调节因子，在RA滑膜中略有下调。然而,SAV1蛋白表达极降低。随后，发现SAV1是磷酸化的，泛素化,并通过与重要的丝氨酸-苏氨酸激酶相互作用而降解，G蛋白偶联受体(GPCR)激酶2(GRK2),在RA中，主要由配体如前列腺素E2（PGE2）诱导的GPCR激活上调。这个过程进一步有助于减少磷酸化，核易位,和YAP的转录效力，并导致异常FLS增殖。GRK2的遗传耗竭或帕罗西汀对GRK2的抑制挽救了SAV1的表达并恢复了YAP磷酸化，最终抑制了RAFLS的增殖和迁移。同样，帕罗西汀治疗可有效减少胶原诱导性关节炎大鼠模型中FLSs的异常增殖，并伴有临床表现的显着改善。总的来说，这些结果阐明了GRK2调节Hippo-YAP信号在FLSs增殖和迁移中的意义,以及GRK2抑制在治疗RA中FLSs驱动的关节破坏中的潜在应用。
