Amelioration of Experimental Autoimmune Arthritis Through Targeting of Synovial Fibroblasts by Intraarticular Delivery of MicroRNAs 140-3p and 140-5p

Abstract

Objective: Synovial fibroblasts (SFs) with aberrant expression of microRNAs (miRNAs) are critical pathogenic regulators in rheumatoid arthritis (RA), and studies analyzing the effect of overexpressing or silencing miRNA expression in arthritis models can contribute to the development of miRNA-based therapeutic strategies. This study was undertaken to examine the hypothesis that miRNAs 140-3p and 140-5p are involved in the pathogenesis of RA, and to determine whether targeting SFs through the intraarticular (IA) delivery of these molecules could ameliorate autoimmune arthritis in mice.

Methods: Synovial tissue samples were obtained from patients with RA. In addition, 2 experimental models in mice were used, collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA). Overexpression of miRNAs 140-3p and 140-5p in SFs and synovial tissue was induced using lentivirus (LV)-mediated transfer of pre-miR-140 precursor molecules.

Results: Lower expression levels of miR-140-3p and miR-140-5p were detected in synovial tissue and SFs from patients with RA and from mice in both arthritis models. In mice with CIA and mice with CAIA, the LV-mediated IA transfer of miR-140-3p and miR-140-5p ameliorated arthritis, as determined by clinical examination and histopathologic evaluations showing a decrease in SF densities. Overexpression of miRNAs 140-3p and 140-5p caused a reduction in expression, with correlated kinetic patterns, of their corresponding target molecules sirtuin 1 and stromal cell-derived factor 1 in the SFs and joints of mice. Transfection of miR-140-3p and miR-140-5p into SFs increased cell apoptosis, reduced proliferation responses and migration abilities, and verified the concept that miR-140 expression is regulated by proinflammatory cytokines.

Conclusion: These results demonstrate that targeting SFs by IA delivery of miRNAs 140-3p and 140-5p can ameliorate autoimmune arthritis. These findings might facilitate the pharmacologic development of molecular-based therapies in RA.