<i>Mir204</i> and <i>Mir211</i> suppress synovial inflammation and proliferation in rheumatoid arthritis by targeting <i>Ssrp1</i>.

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterized by synovial hyperplasia. <i>Mir204</i> and <i>Mir211</i> are homologous miRNAs with the same gene targeting spectrum. It is known that <i>Mir204/211</i> play an important role in protecting osteoarthritis development; however, the roles of <i>Mir204/211</i> in RA disease have not been determined. In the present study, we investigated the effects and molecular mechanisms of <i>Mir204/211</i> on synovial inflammation and hyperproliferation in RA. The effects of <i>Mir204/211</i> on the inflammation and abnormal proliferation in primary fibroblast-like synoviocytes (FLSs) were examined by <i>Mir204/211</i> gain-of-function and loss-of-function approaches in vitro and in vivo. We identified the structure-specific recognition protein 1 (<i>Ssrp1</i>) as a downstream target gene of <i>Mir204/211</i> based on the bioinformatics analysis. We overexpressed <i>Ssrp1</i>and <i>Mir204/211</i> in FLS to determine the relationship between <i>Ssrp1</i> and <i>Mir204/211</i> and their effects on synovial hyperplasia. We created a collagen-induced arthritis (CIA) model in wild-type as well as <i>Mir204/211</i> double knockout (dKO) mice to induce RA phenotype and administered adeno-associated virus (AAV)-mediated <i>Ssrp1</i>-<i>shRNA</i> (AAV-<i>shSsrp1</i>) by intra-articular injection into <i>Mir204/211</i> dKO mice. We found that <i>Mir204/211</i> attenuated excessive cell proliferation and synovial inflammation in RA. <i>Ssrp1</i> was the downstream target gene of <i>Mir204/211. Mir204/211</i> affected synovial proliferation and decelerated RA progression by targeting <i>Ssrp1</i>. CIA mice with <i>Mir204/211</i> deficiency displayed enhanced synovial hyperplasia and inflammation. RA phenotypes observed in <i>Mir204/211</i> deficient mice were significantly ameliorated by intra-articular delivery of AAV-<i>shSsrp1</i>, confirming the involvement of <i>Mir204/211</i>-<i>Ssrp1</i>signaling during RA development. In this study, we demonstrated that <i>Mir204/211</i> antagonize synovial hyperplasia and inflammation in RA by regulation of <i>Ssrp1</i>. <i>Mir204/211</i> may serve as novel agents to treat RA disease.