Therapeutic effect and potential mechanisms of intra-articular injections of miR-140-5p on early-stage osteoarthritis in rats

Abstract

MicroRNAs (miRs) receive extensive attention in osteoarthritis (OA) pathogenesis in recent years, and our previous study confirmed that an intra-articular injection (IAJ) of miR-140-5p alleviates early-stage OA (EOA) progression in rats. This study aims to investigate the therapeutic effect and potential mechanisms of single IAJ (SIAJ) of miR-140-5p on different stage OA and multiple IAJs (MIAJ) of miR-140-5p on EOA. Firstly, the OA model was surgically induced in rats, nine were treated with IAJ of Cy5-miR-140-5p at one week after surgery, and fluorescence distribution was analyzed at different times. Then, 72 rats were treated with SIAJ of miR-140-5p at different stages or MIAJ of miR-140-5p at one week after surgery, and OA progression was evaluated macroscopically and histologically at different times. Finally, the downstream targets and underlying molecular mechanisms of miR-140-5p were predicted by bioinformatics and partially validated. As a result, the intra-articularly injected miR-140-5p entered cartilage and could be taken up by chondrocytes rapidly. IAJ(s) of miR-140-5p improved the behavioral scores, chondrocyte number, cartilage thickness, and pathological scores to varying degrees. Specifically, the earlier a SIAJ of miR-140-5p was administrated, the better the therapeutic effect; meanwhile, MIAJ of miR-140-5p exhibited a better therapeutic effect than SIAJ on EOA. Eighty-four potential target genes and mechanisms of rno-miR-140-5p were predicted, and the effect of miR-140-5p on the potential target genes VEGFA and JAG1 was experimentally validated. Collectively, IAJs of miR-140-5p effectively alleviate EOA progression by modulating multiple biological processes and pathways in rats, representing a promising therapeutic for EOA.