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The Role of MicroRNAs in the Idiopathic Inflammatory MyopathiesJoanna E. Parkes1, Philip Day1, 2, Hector Chinoy3, Janine A. Lamb1 1Centre for Epidemiology, University of Manchester, UK 2Manchester Institute of Biotechnology, University of Manchester, UK3 National Institute of Health Research Manchester Musculoskeletal Biomedical Research Unit, Centre for Musculoskeletal Research, University of Manchester, UKCorresponding Author:Janine A. LambCentre for Epidemiology, University of Manchester, UK 2.722 Stopford BuildingUniversity of ManchesterOxford RoadM13 9PTJanine.Lamb@manchester.ac.uk0161 275 1619?AbstractPurpose of review:The idiopathic inflammatory myopathies (IIM) are a group of rare autoimmune disorders characterised by skeletal muscle weakness and inflammation. MicroRNAs regulate a wide range of developmental and physiological cellular processes. New approaches to investigating the mechanisms involved in IIM, such as investigating the role of microRNAs, are vital for the development of novel therapeutics and/or better diagnostic tools.Recent Findings:Identification of dysregulated microRNAs has lead towards a greater understanding of inflammation, muscle weakness/wasting and extramuscular organ involvement in IIM. Upregulation of immune-related microRNAs in muscle, for example, miR-155 and miR-146, is associated with autoimmunity, while downregulation of myogenic microRNAs, including miR-1 and miR-206, is associated with inhibition of muscle regeneration. Disease mechanisms have been explored by altering in vitro conditions and monitoring microRNA levels of interest or, alternatively, changing microRNA levels and monitoring possible targets. For example, higher levels of cytokines appear to inhibit myogenic microRNAs in muscle and artificially reducing levels of miR-223 increases Protein Kinase C-epsilon (PKC?) levels in keratinocytes.Summary:The exciting expansion of the microRNA field adds to our understanding of IIM pathogenesis and may provide future clinical potential either as diagnostic tools or as therapeutics via use of anti-miRs or synthetic miRNAs.KeywordsmicroRNA, idiopathic inflammatory myopathies, autoimmune, muscle, biomarker IntroductionThe idiopathic inflammatory myopathies (IIM) are a group of rare autoimmune disorders characterised by skeletal muscle inflammation. Drugs used to treat IIM are not specific, borrowed from other more common rheumatic autoimmune diseases. Despite treatment, IIM patients often become and remain weak and disabled with poor quality of life. Non-immune myopathies also can be mistaken for IIM, where misdiagnosis can lead to inappropriate use of immunosuppressant treatments with consequent iatrogenic harm. New approaches to investigating the mechanisms driving the pathology of IIM are thus vital for the development of novel diagnostic and therapeutic approaches. MicroRNA (miRNA) research has rapidly expanded over the last decade. MiRNAs regulate a wide range of developmental and physiological cellular processes including differentiation, proliferation, growth and apoptosis, therefore miRNA dysregulation may induce autoimmunity. Improved understanding of the role of miRNAs and their targets therefore could help to elucidate the pathogenesis of diseases, including IIM. In this review we briefly introduce miRNAs and their function, summarise recent progress in miRNA research in IIM and discuss their potential for diagnostic and therapeutic developments in IIM.MiRNA biogenesis, targeting and functionMiRNAs are 20 to 22 nucleotides long, non-coding, single stranded RNA that are dispersed throughout the genome in intergenic or intronic regions. As shown in Figure 1, primary miRNA (pri-miRNA) is transcribed from genomic DNA by RNA polymerase II. Pri-miRNA is processed into precursor miRNA (pre-miRNA) by the enzyme Drosha and protein DGCR8. Once exported from the nucleus by exportin 5, pre-miRNA is then processed by Dicer and its partner protein TRBP into a duplex. A single strand of this duplex, the mature miRNA, is then loaded into the RNA-induced silencing complex (RISC). Currently, there are 2,588 human mature miRNAs of known sequence on miRBase, a database of all known miRNAs (, accessed 24/07/2015). MiRNAs regulate gene translation by guiding the RISC to the 3’ untranslated region (UTR) of mRNA targets. Binding of a six nucleotide seed sequence complementary to the target mRNA 3’UTR leads to translation suppression or degradation of the transcript [1][2]. Bioinformatic software can be used to predict targets of miRNAs, but these need experimental confirmation with in vitro assays [3]. A single miRNA can target multiple mRNAs, and mRNAs are often targeted by multiple miRNAs, thereby ‘fine-tuning’ biological processes and lending robustness to biological systems [3].MiRNAs in muscle; proliferation, differentiation, regeneration and diseaseA group of miRNAs, known as myomiRs, is found at high levels in skeletal and cardiac muscle [4]. These myomiRs include miR-1, miR-133a/b, miR-206, miR-208, miR-208b, miR-486 and miR-499. MyomiR abundance is regulated by myogenic regulatory factors and myomiRs in turn regulate myogenic regulatory factors in a negative feedback loop, thereby influencing many aspects of myogenesis [5]. For example, miR-1 suppression of histone deacetylase 4 promotes differentiation of myoblasts [6] and miR-1 and miR-206 suppression of Pax7 in satellite cells promotes myogenic differentiation, so resulting in regeneration after injury [7].Given these important physiological roles, it is not surprising that miRNAs also play a role in muscle diseases. For instance, five miRNAs, miR-146b, miR-221, miR-155, miR-214 and miR-222 have been found to be consistently upregulated across ten primary muscle disorders including IIM [8]. These findings suggest an important role for the targets of these miRNAs in maintaining muscle in health and disease.MiRNAs are involved in autoimmunityUp- or down-regulation of miRNAs has been associated with autoimmune responses, and miRNAs act as critical modulators of development and function in the immune system. For example, miR155 is upregulated in peripheral blood mononuclear cells (PBMCs) of patients with the neuromuscular autoimmune condition myasthenia gravis. In an experimental myasthenia gravis (EAMG) mouse model, silencing miR155 decreased production of autoantibodies against acetylcholine receptors, and reduced the severity of myasthenic symptoms, suggesting that miR155 influences B-cell production of specific antibodies [9*]. The miR-181 family appears to play a critical role in fine-tuning the inflammatory response and immune cell development. MiR-181b downregulation in response to pro-inflammatory stimuli regulates NF-κB mediated activation of endothelial cells and vascular inflammation [10]. MiR-181a and miR-181b also regulate B cell maturation, including somatic hypermutations and class switch recombinations. MiR-181a also regulates T cell maturation, including positive and negative selection and T-cell sensitivity [10].MiRNAs are involved in the autoimmune response in IIMStudies of miRNA abundance in IIM have identified dysregulated miRNAs previously associated with autoimmunity. As illustrated in Table 1, an increase in miR-146b and miR-155, which are known to be associated with the innate immune response [3], has been found in three IIM miRNA studies [8,11**,12]. Upregulation of miR-221 and miR-222 has been reported in both IIM [8] and rheumatoid arthritis [13] and upregulation of miR-21 in dermatomyositis (DM) serum [12] and in systemic lupus erythematosus (SLE) CD4+ T cells [15]. These miRNAs may thus regulate, and/or be regulated by, members of common pathways related to autoimmunity.MiR-146a has an established role in innate and adaptive immunity. A recent meta-analysis of a G>C polymorphism, rs2910164, in 24 studies found that the GC or CC genotype was significantly associated with susceptibility to autoimmune disease in Caucasians [21]. In the ‘other diseases’ group comprising studies on multiple sclerosis, systemic sclerosis (SSc), IgA nephropathy, immune thrombocytopenia and IIM, the C allele was associated with significantly increased risk in the allele, homozygote and dominant models[21]. A study of IIM did not find a significant difference in genotype distribution between cases and controls, but did find higher levels of muscle weakness and dysphagia in patients with the CC genotype [16*].MiRNA interactions with cytokinesMiRNA interactions with members of immune pathways may cause, or be the downstream consequence of, the development of autoimmunity. In myasthenia gravis, a pathway from upregulated miR155 to autoimmune related muscle weakness was suggested to occur in a linear fashion via autoantibody production [9*]. In IIM it has been suggested that miRNA levels change in response to autoimmune-related inflammation, and then promote muscle degeneration [11**] (Figure 2). Downregulation of miR-1, miR-133a, miR-133b was observed in all IIM patient samples and miR-206 was downregulated in DM patients [11**]; these myomiRs are established as important in the differentiation and maintenance of skeletal muscle. There was also an increase in expression of inflammatory cytokines. Through further experiments in mouse C212 myoblasts and human skeletal muscle myoblasts, a possible disease mechanism was established whereby increases in TNFα inhibits differentiation of myoblasts into myocytes and myotubes, by means of nuclear factor NF-κB-mediated suppression of miR1, miR133a/b and miR206 [11**]. In contrast to myasthenia gravis, this suggests an alternative route of therapy to silencing the upregulated miRNA, suggesting supplying artificial miRNAs or targeting inflammatory cytokines to prevent miRNA suppression.Influence of miRNAs on differentiation of Th17 in DMCD4+ and CD8+ T cells are known to be involved in DM [22] and levels of each T cell subtype may be regulated by miRNAs [23]. Reduced expression of miR-206 and increased expression of IL-17, RORC and KLF4 mRNAs has been identified in PBMCs from DM patients compared to healthy controls [18]. The relationship between miR-206 and KLF4 also has been investigated in breast cancer stem-like cells [24]. KLF4 promotes miR-206 which inhibits KLF4 in a negative feedback loop. MiR-206 appears to promote tumour initiation and survival [24]. In DM PBMCs, the proportion of Th17 cells also was increased supporting the hypothesis that miR-206 suppresses KLF4, thereby inhibiting Th17 differentiation. With reduction of miR-206, KLF4 is upregulated and promotes production of Th17 cells which secrete IL-17 cytokines and require the transcription factor RORγt (encoded by RORC) to differentiate. However, other Th17 differentiation-associated cytokines (IL-6, TGF-β and IL-23) also were increased in the serum of these patients [17], therefore it is unclear whether downregulation of miR-206 is a cause or consequence of increased serum cytokine concentrations in DM. VCAM-1 expression and early juvenile dermatomyositis (JDM) MiRNA dysregulation may be important in the initiation of IIM disease processes. For instance, downregulation of miR-126 results in increased levels of vascular cell adhesion molecule 1 (VCAM-1) in muscle biopsies from early untreated JDM patients compared to controls, but not in those who had disease for more than two months (also untreated) [20]. VCAM-1 is expressed on active endothelial cells and is an important factor in inflammation. Over-expression of VCAM-1 may explain the capillary abnormalities, reduced ability to regenerate microvasculature and vascular inflammation observed in JDM. A positive feedback loop of inflammation may ensue, as VCAM-1 expression returns to normal two months after disease onset but inflammation continues [20].MiRNAs are associated with skin involvement in DMThe involvement of miRNAs in skin in a variety of skin disorders has been investigated in recent years[25,26]. DM is differentiated from polymyositis (PM) by the presence of highly characteristic skin features such as Gottron’s papules or heliotrope rash. Two studies have analysed miRNAs in Gottron’s papules of DM patients to assess the association of miRNAs with DM skin involvement [18,19].MiR-7Five over-expressed and 27 under-expressed miRNAs were identified in Gottron’s papule skin samples from DM patients compared to healthy controls using, array technology [19]. Further investigation of miR-7, chosen since it has been found to be upregulated in systemic sclerosis skin, showed that it was expressed in normal skin but undetectable in skin from Gottron’s papules. Serum levels of miR-7 also were lower in DM, PM and clinically amyopathic DM (CADM) patients compared to controls [19]. Although no specific mechanism was tested as to how miR-7 might be involved in DM pathogenesis, predicted targets of miR-7 include inflammatory molecules such as fibroblast growth factor 11 and CC chemokine ligand, therefore reduction of miR-7 could result in an inflammatory response.MiR-223A second study of Gottron’s papule skin focussed on miR-223 using an array of 88 miRNAs [18]. MiR-223 was present in normal skin, undetectable in DM skin and downregulated in CADM. Downregulation of miR-223 in DM and CADM skin, but not in psoriatic skin, was confirmed with RT-qPCR. A predicted target of miR-223, protein kinase C? (PKC?), was enriched in the hyperproliferated epidermis of Gottron’s papules. Transfecting normal human epidermal keratinocytes with a miR-223 inhibitor resulted in increased PKC? expression whereas siRNA against PKC? resulted in a reduction in cell numbers. Abnormal proliferation of keratinocytes in Gottron’s papules therefore may be due to downregulation of miR-223 resulting in increased PKC? which promotes keratinocyte growth [24]. Serum levels of miR-223 also were significantly decreased in DM/PM/CADM patients compared to controls [18]. This contrasts with previous findings that miR-223 is a pro-inflammatory miRNA upregulated in the T-cells of rheumatoid arthritis patients [27]. A growing body of evidence has identified that miRNAs, known as oncomiRs, are dysregulated in many types of cancer. Reduced expression of miR-223 has been observed in acute myeloid leukaemia, chronic lymphoid leukaemia, and colon and breast cancer, but miR-223 is overexpressed in metastatic gastric cancer cells [28]. A recent meta-analysis of ten studies found that DM patients have a significantly increased risk of developing lymphatic, haematopoietic, colon and breast cancers (amongst others), but no increased risk was found for gastric or prostate cancer [29]. MiR-223 thus seems to be a tumour suppressive miRNA in these tissues, and this may suggest a link between downregulated miR-223 expression in DM and malignancy.MiRNAs as potential biomarkers Early and accurate diagnosis of IIM is vital for the optimal treatment to be given to prevent worsening of the condition, such as irreversible muscle damage. Histological analysis of biopsies is routinely used as part of diagnosis of IIM, although this is a relatively invasive test. It would be helpful to have also a less invasive diagnostic aid, especially as histological results are sometimes inconclusive [30]. The discovery that miRNAs are stable in serum, resistant to digestion by RNAse A, several cycles of freeze-thaw and high and low pH has opened up the potential use of miRNAs as biomarkers [31]. In this study, miRNA profiles were consistently expressed across healthy individuals of the same species. In samples from healthy individuals the serum miRNA profiles appeared similar to those in blood cells, but in disease states such as cancer or diabetes serum profiles were very different, suggesting that serum miRNA profiles could be used as a ‘fingerprint’ of a particular disease or condition [31]. Within serum, miRNAs are transported to target cells bound to, or within, several types of carriers [27]. Disease-related miRNAs may be associated with particular carrier types such as exosomes, microvesicles, argonaute or low density lipoproteins. Serum from healthy controls and breast cancer patients, when divided into six fractions, yielded more distinct differences in levels of eight miRNAs (measured by RT qPCR) between fractions in cases and controls than in total serum [32]. However, if changes in total miRNA levels are sufficient to differentiate between healthy and disease state, this would present a more easily applicable biomarker for clinical use. To assess whether the serum miRNA profile in an IIM patient reflects the miRNA profile in muscle tissue, samples of each from the same individuals could be analysed for matched miRNA dysregulation. In this way it may be possible to identify a biomarker for IIM or for a subtype or disease stage.This matched analysis approach has been employed in colorectal cancer (CRC), where current screening uses colonoscopy, which is expensive and invasive. Diagnosis of CRC is thus often delayed, leading to poorer treatment outcomes. MiRNAs in tissue or serum have been associated with CRC with either oncogenic or tumour suppressive action. Xu et al. (2014) sought to identify a miRNA dysregulated in both tissue and plasma which could be used as a biomarker of CRC disease [33*]. A subset of dysregulated miRNAs, identified using qRT-PCR based Taqman Low Density MiRNA Arrays in six case tissue samples compared to controls, was compared between 88 matched case tissue and plasma samples and 40 control plasma samples. MiR-375 was significantly downregulated in both tissue and plasma in CRC patients compared to controls, and there was a positive correlation between the two sample types, indicating that miR-375 has potential as a non-invasive CRC biomarker [33*]. MiR-7 and miR-223 may similarly have potential to be used as diagnostic markers in IIM and DM respectively. The finding of miR-7 downregulation in serum of patients with IIM but not in other autoimmune disease [19] is particularly encouraging as serum is a relatively non-invasive sample to obtain and this miRNA seems to differentiate between diseases. RT-qPCR of serum samples from DM, CADM, PM, SLE, SSc and healthy controls showed that miR-21 was upregulated significantly only in DM compared to controls, therefore miR-21 has potential to be used as a biomarker to differentiate between these diseases [14]. Higher miR-21 levels also correlated with higher serum IgG levels, which may indicate an increased inflammatory burden in DM [29]. Urine also has potential for biomarker use. However, miRNA abundance is many times lower in urine than in serum. Differential ultracentrifugation has been used to isolate exosomes in urine, resulting in detection by sequencing of over fifteen times the number of different miRNAs compared to cell-free urine [34*].MiRNAs as therapeuticsPotential miRNA therapies include suppression of miRNAs by anti-miRs or antagomiRs and increase of expression levels by synthetic miRNA mimics. Viruses exploit the cell’s use of miRNAs by introducing their own miRNAs which promote replication of the virus by the host cell. Miravirsen is an anti-miR-122 that currently is being developed for treatment of hepatitis C which has been shown to reduce viral load [35**,36]. However, several factors need to be considered when proposing use of miRNAs as therapeutics. First, individual miRNAs may affect a wide variety of mRNAs, as they do not need complete complementarity to their targets. As a consequence, there may be many non-specific “off-target” effects of artificially influencing miRNA expression [36]. Second, miRNA activity is often context specific. MiR-375 is tumour suppressive via YAP in liver cancer [37] but is oncogenic in breast cancer cells [38]. Delivery of any potential miRNA therapeutic therefore needs to be local, by injection or targeting a specific tissue. Introduction of miRNA mimics (mimetics) into cells not normally expressing that miRNA could have potentially unpredictable or unwanted effects. However, it has been suggested that systemic delivery may be appropriate when targeting immune cells, due to the movement of these cells between the site of inflammation and secondary lymphatic organs via blood and lymph vessels [23]. Third, miRNAs that are conserved across species do not necessarily have the same targets. The let-7 miRNA family represses the oncogene HMGA2 in humans [39], but regulates developmental transitions of hypodermal cells in C.elegans [40] and regulates the development of adult neuromusculature in Drosophila [41]. This complicates the use of model laboratory animals in drug development. Finally, artificial increase of a miRNA using mimics runs the risk of RISC saturation, which may interfere with the expression of other important miRNAs [36].Overall, miRNAs have great potential as therapeutics for a wide variety of diseases including IIM, but development of such treatments is complex and must be approached with caution.ConclusionsMiRNAs represent a new and potentially exciting avenue for future research into IIM. The availability of synthetic miRNA mimics and inhibitors offers the possibility to investigate the impact of miRNAs in vitro. Studies performed in IIM to date show great potential of miRNA research to increase our understanding of disease mechanisms, and to aid diagnosis and act as a target or tool for therapeutic intervention. In coming years, validation and expansion of these studies may change the way we approach IIM research and treatment.Key Points?MiRNAs are small, non-coding, RNAs that regulate a wide range of developmental and physiological cellular processes?MiRNAs have been shown to play a role in myogenesis and in autoimmunity?MiRNA profiling reveals differences between IIM patients (including between disease subgroups) and healthy controls?MiRNAs have potential to be used as diagnostic biomarkers or as targets for therapeutic interventions1 Zeng L, Cui J, Wu H, et al. The emerging role of circulating microRNAs as biomarkers in autoimmune diseases. Autoimmunity 2014;47:419–29. 2 Saito Y, Saito H, Liang G, et al. Epigenetic Alterations and MicroRNA Misexpression in Cancer and Autoimmune Diseases: a Critical Review. Clin Rev Allergy Immunol 2014;47:128–35. 3 Saba R, Sorensen DL, Booth S a. MicroRNA-146a: A Dominant, Negative Regulator of the Innate Immune Response. Front Immunol 2014;5:578. 4 Van Rooij E, Liu N, Olson EN. MicroRNAs flex their muscles. Trends Genet 2008;24:159–66. 5 Güller I, Russell AP. MicroRNAs in skeletal muscle: their role and regulation in development, disease and function. J Physiol 2010;588:4075–87. 6 Chen J-F, Mandel EM, Thomson JM, et al. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet 2006;38:228–33. 7 Chen J-F, Tao Y, Li J, et al. microRNA-1 and microRNA-206 regulate skeletal muscle satellite cell proliferation and differentiation by repressing Pax7. J Cell Biol 2010;190:867–79. 8 Eisenberg I, Eran A, Nishino I, et al. Distinctive patterns of microRNA expression in primary muscular disorders. PNAS 2007;104:17016–21.*9 Wang Y-Z, Tian F-F, Yan M, et al. Delivery of an miR155 inhibitor by anti-CD20 single-chain antibody into B cells reduces the acetylcholine receptor-specific autoantibodies and ameliorates experimental autoimmune myasthenia gravis. Clin Exp Immunol 2014;176:207–21. This study demonstrates inhibition of a microRNA resulting in reduction of autoantibodies in a myasthenia gravis mouse model, showing the potential for targeting microRNAs in therapy for an autoimmune disease. 10 Sun X, Sit A, Feinberg MW. Role of miR-181 family in regulating vascular inflammation and immunity. Trends Cardiovasc Med 2014;24:105–12. **11 Georgantas RW, Streicher K, Greenberg S a, et al. Inhibition of myogenic microRNAs 1, 133, and 206 by inflammatory cytokines links inflammation and muscle degeneration in adult inflammatory myopathies. Arthritis Rheumatol (Hoboken, NJ) 2014;66:1022–33. This study describes a novel mechanism of interaction between microRNAs and cytokines in IIM, highlighting the influence of cytokines on miRNA expression.12 Zhu W, Streicher K, Shen N, et al. Genomic signatures characterize leukocyte infiltration in myositis muscles. BMC Med Genomics 2012;5:53. 13 Pandis I, Ospelt C, Karagianni N, et al. Identification of microRNA-221/222 and microRNA-323-3p association with rheumatoid arthritis via predictions using the human tumour necrosis factor transgenic mouse model. Ann Rheum Dis 2012;71:1716–23. 14 Shimada S, Jinnin M, Ogata A, et al. Serum miR-21 levels in patients with dermatomyositis. Clin Exp Rheumatol 2013;31:161–2.15 Pan W, Zhu S, Yuan M, et al. MicroRNA-21 and microRNA-148a contribute to DNA hypomethylation in lupus CD4+ T cells by directly and indirectly targeting DNA methyltransferase 1. J Immunol 2010;184:6773–81. *16 Okada Y, Jinnin M, Makino T, et al. MIRSNP rs2910164 of miR-146a is associated with the muscle involvement in polymyositis / dermatomyositis. Int J Dermatol 2014;53:300–4. This study links a polymorphism in a miRNA with disease severity, highlighting the potential impact of slight variations in miRNAs on disease.17 Tang X, Tian X, Zhang Y, et al. Correlation between the Frequency of Th17 Cell and the Expression of MicroRNA-206 in Patients with Dermatomyositis. Clin Dev Immunol 2013;2013.18 Inoue K, Jinnin M, Yamane K, et al. Down-regulation of miR-223 contributes to the formation of Gottron’s papules in dermatomyositis via the induction of PKC?. Eur J Dermatology 2013;23:160–8.19 Oshikawa Y, Jinnin M, Makino T, et al. Decreased miR-7 expression in the skin and sera of patients with dermatomyositis. Acta Derm Venereol 2013;93:273–6. 20 Kim E, Cook-Mills J, Morgan G, et al. Increased expression of vascular cell adhesion molecule 1 in muscle biopsy samples from juvenile dermatomyositis patients with short duration of untreated disease is regulated by miR-126. Arthritis Rheum 2012;64:3809–17. 21 Li C, Fu W, Zhang Y, et al. Meta-Analysis of MicroRNA-146a rs2910164 G> C Polymorphism Association with Autoimmune Diseases Susceptibility, an Update Based on 24 Studies. PLoS One 2015;10:1–12. 22 Iaccarino L, Ghirardello A, Bettio S, et al. The clinical features, diagnosis and classification of dermatomyositis. J Autoimmun 2014;48-49:122–7. 23 Baumjohann D, Ansel KM. MicroRNA-mediated regulation of T helper cell differentiation and plasticity. Nat Rev Immunol 2013;13:666–78. 24 Lin C-C, Sharma SB, Farrugia MK, et al. Kruppel-like factor 4 signals through microRNA-206 to promote tumor initiation and cell survival. Oncogenesis 2015;4:e155. 25 Broen JC a, Radstake TRDJ, Rossato M. The role of genetics and epigenetics in the pathogenesis of systemic sclerosis. Nat Rev Rheumatol 2014;10:1–11. 26 Xia J, Zhang W. MicroRNAs in normal and psoriatic skin. Physiol Genomics 2014;46:113–22. doi:10.1152/physiolgenomics.00157.201327 Ta?bi F, Metzinger-Le Meuth V, Massy Z a., et al. MiR-223: An inflammatory oncomiR enters the cardiovascular field. Biochim Biophys Acta - Mol Basis Dis 2014;1842:1001–9. 28 Haneklaus M, Gerlic M, O’Neill L a J, et al. MiR-223: Infection, inflammation and cancer. J Intern Med 2013;274:215–26. 29 Olazagasti JM, Baez PJ, Wetter D a., et al. Cancer Risk in Dermatomyositis: A Meta-Analysis of Cohort Studies. Am J Clin Dermatol 2015;16:89–98. 30 Milisenda JC, Selva-O’Callaghan A, Grau JM. The diagnosis and classification of polymyositis. J Autoimmun 2014;48-49:118–21. 31 Chen X, Ba Y, Ma L, et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 2008;18:997–1006. 32 Ashby J, Flack K, Jimenez LA, et al. Distribution Profiling of Circulating MicroRNAs in Serum. Anal Chem 2014;86:9343–9.*33 Xu L, Li M, Wang M, et al. The expression of microRNA-375 in plasma and tissue is matched in human colorectal cancer. BMC Cancer 2014;14:714. This study shows how circulating miRNA can reflect tissue miRNA dysregulation, highlighting the potential utility of plasma for carrying diagnostic biomarkers.*34 Cheng L, Sun X, Scicluna BJ, et al. Characterization and deep sequencing analysis of exosomal and non-exosomal miRNA in human urine. Kidney Int 2014;86:433–44. This paper describes a method for enhancing miRNA detection in urine which has potential for use in less invasive diagnostics.**35 De Jong YP, Jacobson IM. Antisense therapy for hepatitis C virus infection. J Hepatol 2014;60:227–8. This is the first miRNA based therapy to reach phase 2 clinical trials. This demonstrates the potential of this type of therapy for other diseases.36 Jackson AL, Levin A a. Developing microRNA therapeutics: approaching the unique complexities. Nucleic Acid Ther 2012;22:213–25. 37 Liu AM, Poon RTP, Luk JM. MicroRNA-375 targets Hippo-signaling effector YAP in liver cancer and inhibits tumor properties. Biochem Biophys Res Commun 2010;394:623–7. 38 De Souza Rocha Simonini P, Breiling A, Gupta N, et al. Epigenetically deregulated microRNA-375 is involved in a positive feedback loop with estrogen receptor alpha in breast cancer cells. Cancer Res 2010;70:9175–84. 39 Lee YS, Dutta A. The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev 2007;21:1025–30. 40 Reinhart BJ, Slack FJ, Basson M. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Lett to Nat 2000;:901–6.41 Sokol NS, Xu P, Jan Y-N, et al. Drosophila let-7 microRNA is required for remodeling of the neuromusculature during metamorphosis. Genes Dev 2008;22:1591–6. Table and Figure LegendsTable 1. MicroRNAs dysregulated in IIM. The direction of dysregulation, subtype of IIM, tissue tested and function of microRNAs in tested tissues or previously established associations. * denotes dysregulation which was not statistically significant. CADM, clinically amyopathic dermatomyositis; DM, dermatomyositis; IBM, inclusion body myositis; IIM, idiopathic inflammatory myopathy; JDM, juvenile dermatomyositis; PBMC, peripheral blood mononuclear cells; PM, polymyositis. Figure 1. Biogenesis of mature miRNAs and targeting to mRNA.Primary miRNA (pri-miRNA) is transcribed from genomic DNA by RNA polymerase II, processed into precursor miRNA (pre-miRNA) by Drosha, exported to the cytoplasm via exportin 5, processed into a duplex by Dicer, loaded into the RNA-induced silencing complex (RISC) and then binds target mRNA. Once bound miRNA inhibits translation or induces degradation of the mRNA.Figure 2. Suggested associations between microRNA dysregulation and muscle weakness in myasthenia gravis and idiopathic inflammatory myopathy (IIM). In myasthenia gravis microRNA dysregulation may precede the autoimmune response whereas in IIM the autoimmune inflammatory response may trigger the microRNA dysregulation [9*,11**].AcknowledgmentsNoneFinancial support and sponsorship This study was supported in part by Myositis UK and Arthritis Research UK (18474). JP is supported by a University of Manchester alumni “Research Impact” PhD studentship and President’s Doctoral Scholar Award.Conflicts of interestNone ................
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