The Role of MicroRNA in Rheumatoid Arthritis Pathogenesis

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DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is characterized by chronic joint inflammation and cartilage and bone destruction. The synovial lining cells proliferate and the tissue is infiltrated by macrophages, T cells, and B lymphocytes. These cells are activated and produce inflammatory cytokines, such as tumor necrosis alpha (TNF-) and interleukin beta (IL-1ss). Inhibition of these cytokines improves the clinical symptoms and is effective in preventing progression of tissue destruction, strongly supporting the importance of these cytokines in RA. Despite this important progress, the etiology of RA remains unclear. MicroRNAs (miRNAs) are recently discovered ~22 nucleotide non-coding forms of RNA and are important for a diverse range of biological functions. They exhibit tissue or developmental stage specific expression patterns and are beginning to be associated with human diseases such as cancer or viral infection. However, currently there is limited information on the expression or role of miRNAs in RA. Our preliminary findings show that miRNA-146, a regulator of innate immune responses, is overexpressed in RA synovial tissues, and the expression of miRNA-146 is markedly up-regulated in human rheumatoid arthritis synovial fibroblast (RASF) after stimulation with TNF- and IL-1ss. Furthermore, inhibition of miRNA-146 by antisense oligoribonucleotides revealed therapeutic effects on inflammatory responses both in vitro and in vivo. Based on these observations, we propose the hypothesis that miRNA-146 is a regulator of the chronic immune and inflammatory process in RA and could be a novel therapeutic target for arthritis. We propose the following specific aims: Aim 1: Characterize in detail the expression patterns of miRNA-146 and of other miRNAs that are upregulated in RA synovial tissues; Aim 2: Examine the function of miRNA-146 in regulating synovial cell proliferation, anti-apoptosis and production of inflammatory mediators. Identify novel target genes of miRNA-146 in RASF; and Aim 3: Examine the role of miRNA-146 in inflammatory arthritis in vivo in mice with collagen-induced arthritis (CIA) by introduction of antisense oligoribonucleotides for miRNA-146. Characterization of RA specific miRNAs may help us to understand RA pathogenesis and provide novel therapeutic targets. PUBLIC HEALTH RELEVANCE. Rheumatoid arthritis (RA) is characterized by chronic synovitis and subsequent cartilage and bone destruction; however, its etiology and precise pathogenetic mechanisms remain unclear. Here, we will characterize miRNA-146, which belongs to the recently identified non-coding small RNAs and is upregulated in RA synovial tissue. Determining the role of miRNA-146 and other miRNAs in RA pathogenesis will advance our understanding of mechanisms and open the door for novel therapeutic strategies.