Mir204 and Mir211 suppress synovial inflammation and proliferation in rheumatoid arthritis by targeting Ssrp1

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterized by synovial hyperplasia. Mir204 and Mir211 are homologous miRNAs with the same gene targeting spectrum. It is known that Mir204/211 play an important role in protecting osteoarthritis development; however, the roles of Mir204/211 in RA disease have not been determined. In the present study, we investigated the effects and molecular mechanisms of Mir204/211 on synovial inflammation and hyperproliferation in RA. The effects of Mir204/211 on the inflammation and abnormal proliferation in primary fibroblast-like synoviocytes (FLSs) were examined by Mir204/211 gain-of-function and loss-of-function approaches in vitro and in vivo. We identified the structure-specific recognition protein 1 (Ssrp1) as a downstream target gene of Mir204/211 based on the bioinformatics analysis. We overexpressed Ssrp1and Mir204/211 in FLS to determine the relationship between Ssrp1 and Mir204/211 and their effects on synovial hyperplasia. We created a collagen-induced arthritis (CIA) model in wild-type as well as Mir204/211 double knockout (dKO) mice to induce RA phenotype and administered adeno-associated virus (AAV)-mediated Ssrp1-shRNA (AAV-shSsrp1) by intra-articular injection into Mir204/211 dKO mice. We found that Mir204/211 attenuated excessive cell proliferation and synovial inflammation in RA. Ssrp1 was the downstream target gene of Mir204/211. Mir204/211 affected synovial proliferation and decelerated RA progression by targeting Ssrp1. CIA mice with Mir204/211 deficiency displayed enhanced synovial hyperplasia and inflammation. RA phenotypes observed in Mir204/211 deficient mice were significantly ameliorated by intra-articular delivery of AAV-shSsrp1, confirming the involvement of Mir204/211-Ssrp1signaling during RA development. In this study, we demonstrated that Mir204/211 antagonize synovial hyperplasia and inflammation in RA by regulation of Ssrp1. Mir204/211 may serve as novel agents to treat RA disease.

Noncoding RNAs in skeletal development and disorders

“…MiR-204 and miR-211, two homologous miRNAs with the same target genes, were reported to protect against OA progression [157]. Wang and coworkers continued to determine the effects of two miRNAs on synovial hyperplasia and inflammation [158]. First, they found that expression of miR204/211 was dramatically decreased in synoviocytes of CIA mice, affecting cell migration, apoptosis, proliferation, and inflammatory responses.…”

Deregulation of exosomal miRNAs in rheumatoid arthritis patients

“…Wu et al, (2021) have reported the change in the expression level of miRNA-330-3p in cartilage injury and bone deformities [28]. Previous studies have reported the involvement of miRNA-103a-3p, miRNA-10a-5p, miRNA-204-3p, miRNA-330-3p, and miRNA-19b in synovial PLOS ONE inflammation, cartilage injury, and in inflammatory joint disorder [23][24][25][26][27][28]. No study has been published concerning involvement of exosomal miRNAs, miRNA-103a-3p, miRNA-10a-5p, miRNA-204-3p, miRNA-330-3p, and miRNA-19b in RA patients.…”

“…Zuo et al, (2015) have reported that miRNA-103a-3p controls bone development and inflammation by targeting the RUNX2 gene and acts as the first mechanosensitive microRNA to rescue osteoporosis [26]. Wang et al, (2022) has identified the structure-specific recognition protein 1 (Ssrp1) as the target site of the miRNA-204-3p, and deregulation of miRNA-204-3p results in excessive cellular proliferation and synovial inflammation and ultimately leads to RA [27]. Wu et al, (2021) have reported the change in the expression level of miRNA-330-3p in cartilage injury and bone deformities [28].…”