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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AR056120-02
Application #
7793402
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mao, Su-Yau
Project Start
2009-04-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2011-11-30
Support Year
2
Fiscal Year
2010
Total Cost
$296,102
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Yoshitaka, Teruhito; Kawai, Akira; Miyaki, Shigeru et al. (2013) Analysis of microRNAs expressions in chondrosarcoma. J Orthop Res 31:1992-8
Nakahara, Hiroyuki; Hasegawa, Akihiko; Otabe, Koji et al. (2013) Transcription factor Mohawk and the pathogenesis of human anterior cruciate ligament degradation. Arthritis Rheum 65:2081-9
Miyaki, Shigeru; Asahara, Hiroshi (2012) Macro view of microRNA function in osteoarthritis. Nat Rev Rheumatol 8:543-52
Yamashita, Satoshi; Miyaki, Shigeru; Kato, Yoshio et al. (2012) L-Sox5 and Sox6 proteins enhance chondrogenic miR-140 microRNA expression by strengthening dimeric Sox9 activity. J Biol Chem 287:22206-15
Asada, Maki; Rauch, Alexander; Shimizu, Hirohito et al. (2011) DNA binding-dependent glucocorticoid receptor activity promotes adipogenesis via Kruppel-like factor 15 gene expression. Lab Invest 91:203-15
Higashiyama, Reiji; Miyaki, Shigeru; Yamashita, Satoshi et al. (2010) Correlation between MMP-13 and HDAC7 expression in human knee osteoarthritis. Mod Rheumatol 20:11-7
Miyaki, Shigeru; Sato, Tempei; Inoue, Atsushi et al. (2010) MicroRNA-140 plays dual roles in both cartilage development and homeostasis. Genes Dev 24:1173-85
Yamashita, Satoshi; Andoh, Masataka; Ueno-Kudoh, Hiroe et al. (2009) Sox9 directly promotes Bapx1 gene expression to repress Runx2 in chondrocytes. Exp Cell Res 315:2231-40
Kato, Yoshio; Miyaki, Shigeru; Yokoyama, Shigetoshi et al. (2009) Real-time functional imaging for monitoring miR-133 during myogenic differentiation. Int J Biochem Cell Biol 41:2225-31
Yamasaki, Keiichiro; Nakasa, Tomoyuki; Miyaki, Shigeru et al. (2009) Expression of MicroRNA-146a in osteoarthritis cartilage. Arthritis Rheum 60:1035-41

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