ReviewMicroRNAs in rheumatoid arthritis: Altered expression and diagnostic potential
Introduction
Rheumatoid arthritis (RA) is a polygenic disease with unknown etiology, affecting approximately 1% of the general population. Accordingly to some reports, the incidence of RA differs considerably between geographic areas displaying a possible descending trend from northern to southern latitudes. The occurrence of RA is higher in women than in men and in older individuals in comparison with young people [1].
It is widely accepted that the pathogenesis of RA is characterized by systemic inflammation and autoimmunity with multiple joint lesions. RA is a chronic disease with severe complications and comorbidities, which results in lifelong disability and increased mortality. Therefore, RA, along with other autoimmune diseases, creates a substantial and increasing public health concern as it is associated with significant social and economical impairment [2].
It is supposed that the origin of RA is caused by various environmental factors in genetically predisposed individuals. Thus, different environmental conditions may act as a trigger for the induction of autoimmunity [3]. Recent data strikingly indicate that the pathogenesis of RA is associated with epigenetic dysregulation. Over the past several years, it has become clear that alterations in the expression level of different microRNAs (miRNAs) may contribute to the development of autoimmunity [4], [5], [6], [7], particularly in RA [8], [9].
The initial data, providing a linkage between miRNAs and the pathogenesis of RA, were obtained in 2007, when autoantibodies against GW/P bodies which are associated with miRNA complexes were identified in the serum of patients with RA [10]. Later on, in 2008, Stanczyk et al. revealed significant changes in the expression level of miRNAs in RA and postulated that “the inflammatory milieu may alter miRNA expression profiles in resident cells of the rheumatoid joints” [11]. Subsequent studies were related to the analysis of dysregulation of certain miRNAs within inflamed joints and in the peripheral circulation of patients with RA (Table 1).
Currently, more than 1000 different human miRNAs are validated by intensive research conducted over the last decade [12], and more than 2500 human miRNAs are registered in current databases [13]. Surprisingly, in body fluids, miRNAs show a very high stability since they are present as complexes with proteins or in microvesicles that prevent their degradation by RNases [14]. Thereby, different miRNAs are good candidates for diagnostic purposes, for monitoring of the disease process, and other clinical applications.
The present review aims at highlighting the existing data linking the expression of miRNAs to the detrimental inflammatory response in RA and at discussing the potential of miRNAs as biomarkers for further diagnostic use.
Section snippets
MiRNAs biogenesis and function
MiRNAs are a recently characterized class of non-coding, evolutionarily conserved, endogenously generated, and single-stranded RNAs. Mature forms of miRNAs are about 22 nucleotides in length on an average. MiRNAs are functioning predominantly as negative regulators of the expression of target genes by repressing translation or through direct cleavage of mRNAs. However, there is some evidence suggesting that under certain conditions miRNAs may serve as positive regulators of gene expression [15].
miR-16
Up-regulation of miR-16 was detected in peripheral blood mononuclear cells (PBMCs), plasma, and synovial fluid of RA patients [16], [17], [18]. Within PBMCs, the expression level of miR-16 was considerably higher in monocytes than in the lymphocyte population [16]. The concentration of miR-16 in synovial fluid of RA patients was shown to be significantly lower than in plasma [17]. MiR-16 is a good candidate as a marker of disease activity in patients suffering from RA. Increased levels of
MiRNAs as potential biomarkers of RA
Abnormal expression of different miRNAs has been reported in PBMCs [35], [45], plasma [18], synovial fluid [17], synovial tissue [21], [22], [23], RASFs, [28] and activated immune cells within injured joints [41] in patients suffering from RA. Consequently, miRNAs in peripheral blood or inflamed tissues are considered to be useful as novel biomarkers of RA. The advantages and challenges of miRNAs application for diagnostic purposes are summarized in Table 2.
It appears that circulated miRNAs may
Conclusion and future perspectives
RA always progresses with various manifestations due to its complex pathogenesis and, as a result, is frequently misdiagnosed. The variety of existing criteria for evaluation of the disease state is unsuitable for the detection of early events in RA and even insufficient for prediction of aggravations and remissions of established RA. Therefore, one of the most important challenges in RA is the discovery of new biomarkers for early diagnosis and for prediction of the response to medications.
Take-home messages
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MiRNAs are a class of potent post-transcriptional regulators of gene expression that are involved in various inflammatory conditions, associated with RA pathogenesis.
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MiRNAs are differentially expressed in the peripheral circulation and in the sites of inflammation in RA patients in contrast to healthy individuals and other rheumatic diseases.
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Serum or plasma miRNAs are promising specific, sensitive and non-invasive biomarkers for the monitoring of the disease state and drug response in RA.
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Acknowledgements/Conflict of Interest
None of the authors have any conflicts of interests to declare. This work was funded by the President of the Russian Federation Grants Council, project № MK-3680.2015.7 (Agreement № 14.W01.15.3680-MK), as well as by the federal budget under state order № 0221-2014-0011.
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