ReviewThe role of microRNA in rheumatoid arthritis and other autoimmune diseases
Introduction
MicroRNAs (miRNAs) constitute a recently discovered family of small RNAs, 21–25-nucleotides (nt) in length, that play critical roles in the lives of cells [1]. Since the identification of the miRNA lin-4 as a regulator of developmental timing in the nematode Caenorhabditis elegans (C. elegans) [2], it has become evident that these short non-coding RNAs act post-transcriptionally to regulate eukaryotic gene expression [3]. miRNAs negatively influence mRNA expression by repressing translation or directly leading to cleavage of mRNA sequences. miRNAs are thought to regulate about 30% of the protein-coding genes of the human genome, and individual miRNAs typically target several transcripts rather just one specific gene [4]. Over the last decade, more than 9539 miRNAs have been recognized (http://microrna.sanger.ac.uk/sequences/), including more than 650 expressed in humans. Our understanding of the role of miRNA has expanded to include its involvement in a wide array of biological processes, including cell development, proliferation, differentiation, metabolism and apoptosis [5].
Accumulating data suggest that miRNA control is an important feature of the mammalian immune system. Genetic ablation of the miRNA machinery, as well as loss of deregulation of certain individual miRNAs, severely compromises immune development and regulation, implicating miRNA in the pathophysiology of both immunity and autoimmunity [6], [7], [8]. Among the most common of the autoimmune diseases is rheumatoid arthritis (RA), a systemic illness characterized by diffuse joint inflammation and destruction. Recent studies suggest that miRNA dysregulation may contribute to RA etiopathogenesis. Better understanding of miRNA mechanisms might therefore shed light, not only on the pathogenesis of RA, but also on potential approaches for managing or even suppressing disease.
In this review, we summarize the history of miRNA discovery and biogenesis, with an emphasis on its role in the pathogenesis of inflammatory and autoimmune disorders. We then consider evolving knowledge on the role of miRNA in clinical medicine, as a potential prognostic biomarker in RA and other autoimmune conditions.
Section snippets
miRNA discovery
The occurrence of double-stranded RNAs (dsRNAs) in biological systems was first recognized in the early 1960 s, in the context of viral infections [9], [10]. At that time, the central dogma of molecular biology affirmed the concept that double-stranded DNA (dsDNA) and single-stranded RNA (ssRNA) were utilized for long and short-term information storage, respectively, reserving a role for dsRNA exclusively in the replication of RNA viruses.
Three decades later, the novel concept that dsRNAs
miRNA in the development and regulation of the immune system
miRNAs appear to play pivotal roles in both innate and adaptive immunity, including controlling the differentiation of various immune cell subsets and their immunologic functions.
miRNA in RA and other autoimmune diseases
miRNA dysregulation is linked to auto-immune pathologies that include RA, systemic lupus erythematosus (SLE), multiple sclerosis (MS), primary biliary cirrhosis, ulcerative colitis, and psoriasis (Table 3). The precise mechanisms miRNAs employ to promote (or hinder) autoimmunity have yet to be elucidated. However, several potential mechanisms deserve consideration, including loss or downregulation of miRNA expression due to mutation, epigenetic activation, aberrant processing or transcriptional
miRNA pharmacogenomics
Either disruption or creation of miRNA binding sites can result from many natural single nucleotide polymorphisms (SNPs). Genome-wide surveys of human SNPs in miRNA target sites, and in miRNAs themselves, have identified an appreciable level of variation within predicted miRNA target sites, as well as in target sites that have been experimentally verified for post-transcriptional regulation of mRNAs. miRNA SNPs (miRSNPs) may play both a marker and a functional role, since in some instances such
Conclusion
The identification of small, non-coding RNAs that regulate gene expression, and have essential roles in health and disease, has shifted the dominant protein-centric view of molecular cell biology. Owing to their base-pairing potential, miRNAs can post-transcriptionally modify mRNA structures, allowing for alternative mRNA splicing and modulating interactions of mRNAs with proteins. Basic biomedical research has begun to unravel the central role of miRNA in modulating immune system responses,
Acknowledgments
The authors would like to acknowledge NYU Center of Excellence on Musculoskeletal Disease Initiative Funding. Dr. Greenberg receives salary support from research grants from the NIH (K23AR054412) and the Arthritis Foundation. The authors thank Mr. Shaul Kedem for his assistance with the figure graphics.
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