Micro-RNAs as biomarkers and therapeutic targets for autoimmune arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic, debilitating autoimmune disease that affects 0.3-1% of the world’s population. Approximately 30-40% of RA patients fail to respond well to presently used drugs, and the prolonged use of these drugs may result in serious adverse effects. Additionally, there are inherent limitations in the current biomarkers for RA with regard to their utility in the diagnosis and monitoring of therapeutic response. Therefore, there is an urgent need for novel therapeutic agents and new biomarkers for better management of RA. We proposed that specific micro-RNAs (miRNAs) can serve both these needs. MiRNAs are 19-22 nucleotides in length, transcribed mostly from the non-coding regions of the genome, and increasingly being recognized as master regulators of gene expression. Using the rat adjuvant-induced arthritis (AA) model of RA, we examined the miRNA expression profile of arthritic rats and determined how this profile is modulated following anti-arthritis therapy. We used celastrol, a bioactive triterpenoid derived from a plant extract (celastrus), as a potential therapeutic. Following statistical and bioinformatical analyses, 8 miRNAs that were found to be increased after arthritis development were selected for further study. The expression of 6 of these miRNAs was significantly modulated by celastrol treatment, and the expression profile of the draining lymphoid cells was different from that of serum. We then identified the genes targeted by specific miRNAs, e.g., miR-96. Using transfection of RAW cells (macrophages) and HUVECs (endothelial cells) with miRNA mimics, we identified the target genes whose products play an important role in osteoclastogenesis and angiogenesis, respectively. Network analysis and functional assays further revealed the effects of select miRNAs on these two arthritis-related processes. Interestingly, the levels of expression of some of these miRNA-regulated genes were altered by celastrol, suggesting their involvement in its anti-arthritic effect. We suggest that the above miRNAs may serve as novel biomarkers of disease activity and therapeutic response in arthritis. A subset of these miRNAs could also be targeted for arthritis therapy.