Study on the role and regulation of miR-223 in rheumatoid arthritis and experimental arthritis model

Abstract

MicroRNAs (miRNAs) play roles in autoimmune diseases MiRNA-223 (miR-223) is upregulated in rheumatoid arthritis (RA) patients and is involved in osteoclastogenesis that contributes to erosive disease Here we tested the feasibility of using lentiviral vectors expressing the miR-223 target sequence (miR-223T) to suppress miR-223 activity as a therapeutic strategy in a mouse model of collagen-induced arthritis (CIA) Levels of miR-223 expression in the synovial tissue of RA and osteoarthritis (OA) patients as well as ankle joints of CIA mice were determined by quantitative RT-PCR Lentiviral vectors expressing miR-223T (LVmiR-223T) or luciferase shRNA (LVshLuc) serving as a control vector were injected intraperitoneally into CIA mice The treatment responses and disease-related bone mineral density were monitored Levels of NFI-A a direct target of miR-223 and macrophage colony-stimulating factor receptor (M-CSFR) critical for osteoclastogenesis were detected by immunohistochemistry and quantitative RT-PCR Osteoclasts were assessed by TRAP staining MiR-223 expression was significantly higher in the synovium of RA patients and ankle joints of CIA mice compared with OA patients and normal mice LVmiR-223T reduced the arthritis score histologic score miR-223 expression osteoclastogenesis and bone erosion in CIA mice Downregulation of miR-223 with concomitant increases in NFI-A levels and decreases in M-CSFR levels was detected in the synovium of LVmiR-223T-treated mice We also found that miR-223 is essential for the hyperproliferation of CIA synovial fibroblasts (SFs) When miR-223 is suppressed the proliferation of CIA SF is reduced through the downregulation of Akt/mTOR pathway This report is the first to demonstrate that lentivirus-mediated silencing of miR-223 can reduce disease severity of experimental arthritis Furthermore our results implicate that inhibition of miR-223 activity may be further explored as a therapeutic strategy for patients with RA

Date of Award	2014 Jan 16
Original language	English
Supervisor	Chao-Liang Wu (Supervisor)