The Role of MicroRNA in Rheumatoid Arthritis Pathogenesis

描述（由申请人提供）：类风湿性关节炎（RA）以慢性关节炎症和软骨和骨破坏为特征。滑膜衬里细胞增生，组织被巨噬细胞、T细胞和B淋巴细胞浸润。这些细胞被激活并产生炎性细胞因子，如肿瘤坏死α (TNF-)和白细胞介素β (IL-1ss)。抑制这些细胞因子可改善临床症状，有效防止组织破坏的进展，有力地支持了这些细胞因子在RA中的重要性。尽管取得了这一重要进展，但RA的病因仍不清楚。MicroRNAs （miRNAs）是最近发现的约22个核苷酸的非编码形式的RNA，在多种生物学功能中起着重要作用。它们表现出组织或发育阶段特定的表达模式，并开始与癌症或病毒感染等人类疾病有关。然而，目前关于mirna在RA中的表达或作用的信息有限。我们的初步研究结果表明，miRNA-146作为先天免疫反应的调节因子，在RA滑膜组织中过表达，并且在TNF-和IL-1ss刺激后，miRNA-146在人类风湿关节炎滑膜成纤维细胞（RASF）中的表达显著上调。此外，反义寡核苷酸抑制miRNA-146在体外和体内均显示出对炎症反应的治疗作用。基于这些观察结果，我们提出miRNA-146是RA慢性免疫和炎症过程的调节因子，可能是关节炎的新治疗靶点。我们提出以下具体目标：目标1：详细表征miRNA-146和其他mirna在RA滑膜组织中上调的表达模式；目的2：研究miRNA-146在调节滑膜细胞增殖、抗凋亡和炎症介质产生中的功能。在RASF中发现新的miRNA-146靶基因目的3：通过引入miRNA-146的反义寡核苷酸，研究miRNA-146在胶原诱导关节炎（CIA）小鼠体内炎症性关节炎中的作用。RA特异性mirna的鉴定可能有助于我们了解RA的发病机制并提供新的治疗靶点。

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.