Clin Rheumatol (2015) 34:615–628 DOI 10.1007/s10067-015-2898-x

REVIEW ARTICLE

MicroRNAs in rheumatoid arthritis Eisa Salehi & Rahil Eftekhari & Mona Oraei & Alvand Gharib & Katayoon Bidad

Received: 27 December 2014 / Revised: 9 February 2015 / Accepted: 9 February 2015 / Published online: 4 March 2015 # International League of Associations for Rheumatology (ILAR) 2015

Abstract The role of genetic and epigenetic factors in the development of rheumatic diseases has been an interesting field of research over the past decades all around the world. Research on the role of microRNAs (miRNAs) in rheumatoid arthritis (RA) has been active and ongoing, and investigations have attempted to use miRNAs as biomarkers in disease diagnosis, prognosis, and treatment. This review focuses on experimental researches in the field of miRNAs and RA to present the data available up to this date and includes researches searched by keywords BmicroRNA^ and Brheumatoid arthritis^ in PubMed from 2008 to January 2015. All references were also searched for related papers. miRNAs are shown to act as proinflammatory or anti-inflammatory agents in diverse cell types, and their role seems to be regulatory in most instances. Researchers have evaluated miRNAs in patients compared to controls or have investigated their role by overexpressing or E. Salehi : R. Eftekhari Immunology Department, School of Medicine, Tehran University of Medical Sciences, Poursina St, Ghods St, Enghelab Ave, Tehran 1417613151, Iran M. Oraei Immunology Department, School of Public Health, Tehran University of Medical Sciences, Poursina St, Ghods St, Enghelab Ave, Tehran 1417613151, Iran A. Gharib Naamdar Medical Diagnostic Lab, Tehran University of Medical Sciences, No. 118, Fathi Shaghaghi St, Yousef Abad Ave, Tehran, Iran K. Bidad (*) Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, No. 62, Gharib St, Keshavarz Blvd, Tehran 14194, Iran e-mail: [email protected] K. Bidad e-mail: [email protected]

silencing them. Multiple targets have been identified in vivo, in vitro, or in silico, and the researches still continue to show their efficacy in clinical settings. Keywords Autoimmunity . Biomarkers . Immunology . Inflammation . MicroRNA . miRNA . Rheumatoid arthritis

Introduction Regulation of human gene transcription and translation is a quite complex phenomenon, and microRNAs (miRNAs) are considered as one part of this complicated process. MiRNAs can have multiple targets, and a single gene may be a target of many miRNAs. Innate and adaptive immune responses and diverse cellular functions including cell differentiation, proliferation, metabolism, homeostasis, apoptosis, and tumorigenesis are regulated by miRNAs. MiRNAs act individually or in clusters, and clustered miRNAs are more efficient at regulating complex processes [1]. RA is a chronic inflammatory disease characterized by synovial inflammation eventually leading to joint destruction with severe functional deterioration and high morbidity and mortality. Rheumatoid synovium consists of fibroblast-like synoviocytes (FLSs) and macrophage-like synoviocytes and leukocytes. These cells are the source of cytokines, chemokines, and transcription factors that contribute to the pathogenesis of RA [2]. The prolonged life span of cells in synovium is also a major contributing factor to the ongoing joint inflammation and destruction [3]. Multiple studies have shown the effect of proinflammatory cytokines (tumor necrosis factor (TNF)-α, IL-1β, and IL-6) on RA pathogenesis, and IL-17 has particularly been recognized as a principal factor in activation of receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB)

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ligand (RANKL) and osteoclasts and thus bone destruction and inflammation in RA [4]. miRNAs have also been implicated in RA pathogenesis, and their expression has been evaluated in blood, joints, synovium, and different cell types in RA. Although current treatments for RA consisting of cytokine inhibitors, B cell-depleting agents, and T cell costimulatory blocking agents have had positive therapeutic effects, miRNAs are supposed to have the same performance with probably better results and less side effects.

Method Medline database was searched through PubMed (http://www. ncbi.nlm.nih.gov/pubmed/) by keywords BmicroRNA^ and Brheumatoid arthritis^ from 2008 to January 2015 by two independent investigators, and related references of included papers were also considered. Language was restricted to English, and no limitation was imposed on study types. The final inclusion was based on the relevance of the experiments performed to the aim of this review and full-text availability.

Findings related to miRNAs in RA Multiple studies have evaluated miRNAs in autoimmune diseases, and the results have been, in many instances, controversial. Here, we review the recent researches in the field of miRNAs and RA in numerical order. miR-16 In RA, increased levels of miR-16 have been reported in plasma, peripheral blood mononuclear cells (PBMC), and synovial fluid of patients compared to healthy or disease controls and even linked to disease activity [5, 6]. In a study by Filkova et al., serum miR-16 was reported to be lower in early RA patients compared to established RA patients and healthy controls (HC). The baseline levels were positively correlated with greater improvement in disease activity and negatively correlated with anti-citrullinated protein antibody (ACPA) [7] (Table 1). miR-17-92 cluster This cluster also known as BoncomiR-1^ consists of miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92a-1. This cluster has vital roles in the development of the heart, lungs, and B cells and also in the cell cycle, proliferation, and apoptosis. In humans, this cluster and its members, miR-20a, miR-19a, miR-19b, and miR-18, have been shown to be downregulated in RA FLS in response to Toll-like receptor (TLR) stimulation [10].

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Of the cluster, miR-18a transfection has been shown to upregulate matrix metalloproteinase (MMP)-1; IL-6; IL-8; monocyte chemoattractant protein (MCP)-1; and Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) and increase chemoattractant potential of RA synovial fibroblasts (RASFs) leading to matrix infiltration and degradation. miR-18a enhances NF-κB signaling in RASFs by repressing NF-κB pathway inhibitor, tumor necrosis factor, alpha-induced protein 3 (TNFAIP-3), resulting in joint inflammation and destruction [8]. This cluster has also been shown to be downregulated in bacterial lipoprotein (BLP)-activated RA FLS. miR-19a/b negatively regulates IL-6 production and thus acts as an anti-inflammatory agent [9]. Gantier et al. recently suggested a role for endogenous miR-19b in positive regulation of NF-κB signaling through negative regulators of NF-κB which causes proinflammatory cytokine production and inflammation [17]. miR-20 is considered to be an anti-inflammatory regulator by targeting apoptosis signal-regulating kinase 1 (ASK1), a member of the kinase family, activated in response to stress signals [10]. The prediction algorithm, TargetScan, expects that miR-17∼92 cluster might negatively regulate ASK1, one of the main players of inflammation in RA [1] (Table 1).

miR-22 Lin et al. have defined a p53/miRNA-22/Cyr61 axis in RA synovial tissue and showed that somatic mutations in the p53 gene observed in RA synovium lead to the downregulation of miR-22 and thus overexpression of Cyr61 at the posttranscriptional level. Cyr61 promotes FLS proliferation in an autocrine/paracrine manner and also stimulates FLS to produce IL-6 and deviates cells toward Th17 lineage [11] (Table 1).

miR-23b miR-23b is an anti-inflammatory miRNA which is downregulated in RA compared to osteoarthritis (OA) and HC. Overproduction of IL-17 can potently suppress miR-23b leading to overexpression of transforming growth factor (TGF)-β-activated kinase 1/MAP3K7-binding protein (TAB)3, IκB kinase (IKK)-α and TAB2, and inflammatory cytokines [12]. In a study by Ham et al., miR-23b transfection with a small molecule (H-89) could inhibit protein kinase A (PKA) signaling and induce the differentiation of synovial fluid-derived mesenchymal stem cells (SFMSCs) into chondrocytes with therapeutic effects on degenerative processes in RA and OA patients [13] (Table 1).

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miR-24 miR-24 is supposed to have inflammatory roles by regulating TGF-β1 and targeting of Furin, which is required for peripheral immune tolerance of T cells. This miRNA is shown to be higher in RA patients compared to OA and systemic lupus erythematosus (SLE) patients and has been proposed as a potential diagnostic marker of RA even in ACPA-negative patients [14] (Table 1). miR-30a miR-30a was downregulated in RA compared to OA synovial tissues, and this was associated with increase in the expression of the autophagic marker, Beclin-1, and increased autophagy and apoptotic resistance, suggesting a mechanism for reduced apoptosis in RA synovial tissues [15] (Table 1). miR-34 miR-34a is identified as a regulator of cell death with controversial roles as inducer or protector for apoptosis. In a study on synovial fibroblasts, miR-34a, b, and c expression levels were not significantly different in RA compared to OA patients, while passenger strand miR-34a* was significantly downregulated in RA compared to OA synovial fibroblasts. Downregulation of miR-34a* results in unopposed and increased expression of X-linked inhibitor of apoptosis protein (XIAP) as an apoptosis inhibitor and caused death resistance of synovial fibroblasts [3]. miR-34b, a miRNA associated with cell cycle, apoptosis, and senescence, has been found to be overexpressed in RA T cells compared to normal T cells, and it has been shown to suppress cAMP response element-binding (CREB) protein expression. CREB is a transcription factor involved in synovial cell dysfunction [16] (Table 1). miR-124a Evidence shows that miR-124a expression is lower in RA FLS compared to OA FLS, leading to increased expression of cyclin-dependent kinase (CDK)-2 and facilitated secretion of MCP-1 and an increase in RA synovial cell proliferation and the inflammation [2]. Epigenetic studies have shown higher promoter methylation in miR-124a in RA synovial tissues compared to OA and HC synovial tissues, implying a role for epigenetic dysregulation in RA pathogenesis [18] (Table 2). miR-125 miR-125b is overexpressed in serum and blood samples of RA patients compared to healthy donors or patients with

617

OA. High expression of miR-125b is suggested to be used as a predictive biomarker for a good response to rituximab therapy [19], and plasma miR-125a-5p is considered as a potential diagnostic marker of RA [14] (Table 2). miR-132 In RA PBMC, miR-132 was shown to be increased almost twice compared to HC [5] while, in plasma, the levels of miR-132 were lower in RA and OA compared to HC. The miR-132 levels in RA synovial fluid were significantly lower than those in the plasma, and it was concluded that plasma levels could differentiate RA and OA patients from HC. miR132 might play a role in the systematic conditions related to joint inflammation [6]. miR-133a, miR-142-3p, and miR-142-5p These miRNAs were expressed more potently in RA FLS compared to OA [2]. miR-146a A variety of microbial components or cytokines can induce this miRNA, and different genes in diverse cell types are known to be targets of miR-146a. Most studies performed in RA confirm that this miRNA increases in plasma, peripheral blood, macrophages, B cells, T cells, CD4+ T cells, Th17 cells, and synovium of RA patients [20–22] and is required for the suppressive function of regulatory T cells (Treg cells) and inhibition of Th1 responses [23, 24]. In T cells of RA patients, the levels of miR-146a are shown to be negatively correlated to the levels of Fas-associated factor (FAF) 1 and the increase in this miRNA ultimately results in suppressed T cell apoptosis contributing to inflammation in RA. The levels of miR-146a are also positively correlated to TNF-α both in peripheral blood and synovial fluid, and this is a critical factor for induction and maintenance of inflammation [20]. It has been reported in a couple of studies that the main two targets of miR-146a, TNF receptor-associated factor (TRAF)-6, and interleukin-1 receptor-associated kinase (IRAK)-1 remain unchanged in contrast to TNF-α. It has been hypothesized that miR-146a might not be acting as a negative regulator of inflammation in RA, but as an inflammatory agent by induction of TNF-α [5, 20]. It has also been hypothesized that inability of miR-146a to regulate its targets leads to prolonged TNF-α production [5]. In a study by Nakasa et al. on 2011, it was shown that miR146a transfection could downregulate transcription factors and cause osteoclastogenesis suppression. This study also showed the in vivo efficacy of double-stranded miR-146a in suppression of joint destruction in collagen-induced arthritis mice model [25]. In conclusion, in spite of miR-146a

RA, SLE, OA, and HC plasma

RA and OA synovial tissues

Synovial fibroblasts from RA and OA patients

miR-24

miR-30a

miR-34a*

SFMSCs from OA and RA patients

Inflammatory lesions of RA, OA patients, Downregulated and HC

miR-23b

Downregulated

Decreased

Increased

Transfection

Downregulated

FLS

miR-22

Downregulated Transfection

LPS- and BLP-activated RA FLS

Transfection

Downregulated

miR-20a

BLP-activated RA FLS

miR-19a/b cluster BLP- and LPS-stimulated RA FLS

Transfection

Sera of treatment-naïve early RA patients, Decreased established treated RA patients and HC

TNF-α-stimulated RASFs

-Lower levels in early RA compared to established RA and HC -Correlation of higher levels at baseline with a greater improvement in disease activity -Negative correlation of baseline levels with ACPA -Upregulation of MMP-1, IL-6, IL-8, MCP-1, and RANTES -Repression of NF-κB pathway inhibitor TNFAIP-3 -NF-κB signaling enhancement -Decreased miR-19a and miR-19b expression and upregulation of TLR2 expression -Decreased TLR2 protein expression -Significant downregulation of IL-6 and MMP-3 -Decreased miR-20a expression and ASK1 upregulation -Decreased ASK1 protein -Decreased p38 phosphorylation -Decline in IL-6 and CXCL10 release by LPS-activated RA FLS -Decline in IL-1β and TNF-α release by activated THP-1 cells in response to LPS -Failure of mutant p53 in RA synovial tissue to upregulate miR-22 transcription -Overexpression of Cyr61 leading to Th17 cell differentiation -Inverse correlation between IL-17 and miR-23b expression in FLS -Suppression of IL-17-, TNF-α-, and IL-1β-induced NF-κB activation and inflammatory cytokine expression Differentiation of SFMSCs into chondrocytes able to repair damaged cartilage -Increased in RA compared to OA and SLE -miR-24 and miR-125a-5p as potential diagnostic markers for RA diagnosis -Significant decrease in RA compared to OA -Inverse correlation with Beclin-1 mRNA -Positive correlation of the percentage of apoptotic cells and miR-30a expression -Decreased apoptosis and upregulated autophagy in synovial tissues -Low expression levels result in decreased apoptosis of RASFs -Expression decreases by methylation -TNF-α, IL-1β, and TLR ligands do not induce miR-34a* -Apoptosis resistance of RASFs

Increased

Plasma

miR-18a

-Increased expression compared with healthy and disease control individuals -High levels correlated with active disease -3.4-fold increased expression in monocyte/macrophages compared to lymphocytes Significant inverse correlation with disease activity

Increased

PBMC of RA patients and healthy and disease controls

Results

miR-16

Changes

Tissue or cell lines

Researches on miRNAs 16, 18a, 19a/b, 20a, 22, 23b, 24, 30a, 34a*, and 34b in RA

miRNA

Table 1

Murata et al. [6] Filková et al. [7]

– –

Zhu et al.[12]

Lin et al. [11]

Philipe et al. [10]

Philippe et al. [9]

XIAP upregulation

Beclin-1

Niederer et al. [3]

Xu et al. [15]

Inhibiting PKA signaling Ham et al. [13] PRKACB – Murata et al. [14]

Suppression of TAB3, IKK-α, and TAB2

Cyr61

ASK1

TLR2 mRNA

Trenkmann et al. [8]

Pauley et al. [5]

–

TNFAIP-3 and NF-κB

References

Targets

618 Clin Rheumatol (2015) 34:615–628

Transfection Jurkat cells

619 ACPA anti-citrullinated protein antibody; ASK1 apoptosis signal-regulating kinase 1; BLP bacterial lipoproteins; CXCL10 C-X-C motif chemokine 10; CREB cAMP response element binding; FLS fibroblast-like synoviocytes; HC healthy controls; IKK IκB kinase; LPS lipopolysaccharide; MCP monocyte chemoattractant protein; MMP matrix metalloproteinase; NF-κB nuclear factor kappa-lightchain-enhancer of activated B cells; OA osteoarthritis; PBMC peripheral blood mononuclear cells; PKA protein kinase A; PRKACB protein kinase A catalytic subunit B; RA rheumatoid arthritis; RANTES Regulated on Activation, Normal T Cell Expressed and Secreted; RASF RA synovial fibroblasts; SCD5 stearoyl-CoA desaturase 5; SFMSC synovial fluid-derived mesenchymal stem cells; SLE systemic lupus erythematosus; TAB TGF-β-activated kinase 1/MAP3K7-binding protein; TNFAIP-3 tumor necrosis factor, alpha-induced protein 3; Th17 T helper 17; TLR Toll-like receptor; TNF-α tumor necrosis factor-α; TRAIL TNF-related apoptosis-inducing ligand; XIAP X-linked inhibitor of apoptosis protein

CREB protein

Lu et al. [16] SCD5 Overexpressed RA and HC T cells

-Enforced expression promotes apoptosis in FasL- and TRAIL-stimulated RASFs -Overexpression in RA T cells compared to normal T cells -Microarray of predicted targets showed decreased SCD5 in RA T cells -Suppression of CREB protein expression miR-34b

Table 1 (continued)

Changes Tissue or cell lines miRNA

Results

Targets

References

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upregulation in different RA cell types [2, 4–6, 20–22, 26], in vivo exogenous miR-146a seems to inhibit osteoclastogenesis [25] suggesting controversial roles for this miRNA (Table 3). miR-155 This miRNA was primarily known as an oncogenic miRNA or a miRNA involved in hematopoiesis and was later shown to be expressed in innate and adaptive immune cells [26]. miR155 is required for Treg cell homeostasis in the presence of IL2 and has been attributed to memory Treg phenotype [27, 28]. It is extremely upregulated during maturation of LPSactivated human monocyte-derived dendritic cells (DC) and targets TLR/IL-1 inflammatory pathway and TAB2, leading to downregulation of inflammatory cytokine production after microbial stimulation [29]. miR-155 is expressed in autoimmune diseases such as multiple sclerosis, SLE, and RA, and expression of this miRNA was found to be higher in synovial cells and tissues, PBMC, CD4+ T cells, and Th17 cells in RA patients compared to HC or OA patients [6, 30, 31]. miR-155 has also been identified as a potent inhibitor of Src homology 2-containing inositol phosphatase (SHIP) pathway, leading to increased proinflammatory cytokine synthesis and development of autoreactive T cells and chronic inflammation. The miR-155/SHIP pathway might lead to proinflammatory activation of myeloid cells in inflammatory arthritis [30]. In the year 2008, the association of miR-155 and MMP was reported among the RA patients. Increased expression of miR155 and its overexpression by exposure to proinflammatory cytokines and TLR ligands could suppress MMPs (MMP-1 and MMP-3) and lead to modulation of joint inflammation with a defending function in RASF-mediated tissue damage in RA [26]. Long et al., in 2013, reconfirmed miR-155 overexpression in RASF and PBMC compared to HC and its upregulation in response to TNF-α, as well as its effect on MMP3 downregulation and its protective potential by suppressing proliferation and invasion of RA FLS [31]. Li et al., in 2013, could again verify increased expression of miR-155 in RA PBMC compared to OA and HC and could show the correlation between this miRNA and TNF-α and IL-1β production in PBMC through suppression of suppressor of cytokine signaling (SOCS)1 expression [32]. Contrary to findings confirming the protective role of miR-155 in RA, in vivo mice studies showed a pathogenic role for miR-155 in collageninduced arthritis (CIA) [33]. miR-155 and its star form, miR-155*, are the most potently induced miRNAs in primary human plasmacytoid DC and have opposite effects on interferon (IFN) production in these cells. Following TLR-7 stimulation, miR-155* is firstly induced, leading to IFN-α production. At later stages, miR-

Increased

Increased Increased

-Upregulation in RA FLS compared to OA FLS

-Lower expression of RA FLS compared to OA FLS -Overexpression leads to suppression of CDK-2 and MCP-1, downregulation of angiogenin, and upregulation of VEGF -Higher promoter methylation pattern of miR-124a in RA compared to OA and HC miR-24 and miR-125a-5p as potential diagnostic markers for RA diagnosis -Elevated in RA patients compared to OA and HC -Increased in patients with other forms of chronic inflammatory arthritis -High serum levels at flares associated with good clinical response to rituximab treatment -Increased expression levels of miR-132 compared with healthy and disease control individuals -4.2-fold increased expression in monocyte/macrophages compared to lymphocytes Lower expression in RA and OA patients compared to HC -Lower expression in synovial fluid compared to plasma -No correlation between plasma and synovial fluid miRNAs -Upregulation in RA FLS compared to OA FLS -Upregulation in RA FLS compared to OA FLS

Results

Murata et al. [14] Duroux-Richard et al. [19]

Pauley et al. [5]

Murata et al. [6]

– –

–

–

–

Nakamachi et al. [2]

Zhou et al. [18]

–

– –

Nakamachi et al. [2]

Reference

CDK2, MCP-1, Angiogenin and VEGF

Targets

CDK-2 cyclin-dependent kinase 2; FLS fibroblast-like synoviocytes; HC healthy controls; MCP monocyte chemoattractant protein; OA osteoarthritis; PBMC peripheral blood mononuclear cells; RA rheumatoid arthritis; SLE systemic lupus erythematosus; VEGF vascular endothelial growth factor

RA and OA FLS

miR-142-5p

–

RA and OA synovial fluid and plasma

RA and OA FLS RA and OA FLS

Decreased

RA, OA, and HC plasma

miR-133a miR-142-3p

Increased

PBMC of RA patients and healthy and disease controls

miR-132

Increased

Blood and serum of HC, RA, and other rheumatic diseases and arthritis patients

miR-125b

Increased

RA, SLE, OA, and HC plasma

Increased methylation

RA, OA, and HC synovial tissues

miR-125a-5p

Decreased

RA and OA FLS

miR-124a

Changes

Tissue or cell lines

Researches on miRNAs 124a, 125a-5p, 125b, 132, 133a, 142-3p, and -5p in RA

miRNA

Table 2

620 Clin Rheumatol (2015) 34:615–628

Increased

Increased

Increased Increased

Increased

Increased

Increased Transfection

Increased

RA and OA synovial fibroblasts, synovial tissue, and monocytes

PBMC of RA patients and healthy and disease controls

RA and OA FLS

RA and OA synovial fluid RA and OA plasma and synovial fluid

CD4+ T cells

PBMC and synovium of RA and OA patients

RA, OA, and HC PBMC

PBMC in osteoclastogenesis culture system

Inflammatory lesions of RA and OA patients and HC Tregs

-Upregulation in autoimmune disease samples compared to representative controls -miR-146a diminished upregulation contributes to proinflammatory phenotype of Tregs via increased STAT1 activation -Lower miR-146a levels in early RA compared to established RA and HC -No difference between established RA and HC

Higher in RA compared to OA -Higher in plasma compared to synovial fluid -Synovial fluid to plasma ratio was higher in RA patients compared to OA patients -Synovial fluid to plasma ratio was inversely correlated with number of tender joints -Suppressed T cell apoptosis via FAF1 -miR-146a increased expression was closely correlated with increased levels of TNF-α in peripheral blood and synovial fluid -Higher expression in RA PBMC compared to OA and HC -Higher expression in RA synovium compared to OA -Correlation with IL-17 in patients with early stage of RA and high disease activity -miR-146a expression in the IL-17-producing T cells of the RA synovium -Higher expression in RA compared to OA and HC -Positive correlation with TNF-α, ESR, and disease activity -Osteoclastogenesis suppression

-Is highly expressed in RA, less highly expressed in OA, and normal synovial tissue -Cells positive for miR-146a were primarily CD68+ macrophages but included several CD3+ T cell subsets and CD79a+B cells -Expression in PBMC mimicked RA synovial tissue and fibroblasts Overexpression in RA synovial fibroblasts and tissue compared to OA synovium -Upregulation after LPS- or IL-1-stimulation -Increased expression compared with healthy and disease control individuals -High levels correlated with active disease -2.8-fold increased expression in monocyte/macrophages compared to lymphocytes -Upregulation in RA FLS compared to OA FLS

Notes

Abou-Zeid et al. [22]

–

Zhou et al. [24] Filková et al. [7]

STAT1 –

Zhu et al. [12]

Nakasa et al. [25]

Niimoto et al. [4]

–

Downregulation of c-Jun, NFATc1, PU.1 and TRAP –

Li et al. [20]

Murata et al. [6]

–

FAF1

Nakamachi et al. [2]

–

Stanczyk et al. [26]

–

Pauley et al [5]

Nakasa et al. [21]

–

TRAF6 and IRAK1 expression: similar to controls

Reference

Targets

ESR erythrocyte sedimentation rate; FAF1 Fas-associated factor-1; FLS fibroblast-like synoviocytes; HC healthy controls; IRAK1 interleukin-1 receptor-associated kinase 1; LPS lipopolysaccharide; NFATc1 nuclear factor of activated T cells c1; OA osteoarthritis; PBMC peripheral blood mononuclear cells; RA Rheumatoid arthritis; STAT1 signal transducer and activator transcription 1; TNF-α tumor necrosis factor alpha; TRAP tartrate-resistant acid phosphatase, TRAF6 TNF receptor-associated factor 6; Tregs regulatory T cells

Sera of treatment-naïve early RA patients, established treated RA patients, and HC

Increased

Synovial tissue of RA and OA patients and normal subjects

Decreased

Changes

Researches on miR-146a in RA

Tissue or cell line

Table 3

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622

155 peaks and its increase causes rapid decline in IFN-α expression. So, both strands of miR-155 are tightly regulated by TLRs as external stimulus, and they contribute in the regulation of host responses [34]. miR-155 aberrant expression has been associated with a couple of autoimmune diseases. Davis et al. have investigated if miR-155 reduction could have therapeutic effects. They inspected the effects of methylprednisolone (MP) on CD4+ T cells and showed that MP, by decreasing miR-155, could increase SOCS1, a known target of miR-155 and so decrease Janus kinase (JAK)/signal transducer and activator transcription (STAT) signaling and IFN-γ production by activated T cells [35]. It seems that appropriate levels of this miRNA might be involved in maintaining normal immune function (Table 4). miR-203 miR-203 is known as a suppressor of multiple malignancies with the effect on MMPs and IL-6 in the immune system. It has been reported to be upregulated in synovial fibroblasts of RA patients compared to OA patients, increasing IL-6 and MMPs leading to joint pathology [36] (Table 5). miR-221/222 cluster and miR-223 miR-221/222 cluster has been reported to be overexpressed in RA synovial fibroblasts in comparison to OA [37]. Murata et al. reported increased concentrations of miR-223 in RA and OA plasma compared to synovial fluid and higher concentration in RA compared to OA and inverse correlation with disease activity [6]. In adaptive immune responses, it was found to be significantly upregulated in peripheral T cells of RA patients. This miRNA was expressed at higher levels in naïve CD4+ T cells and almost was not detectable in Th17 cells [38]. A study by Lu et al. has also shown that overexpression of miR-223 in RA patients, by decreasing insulin growth factor-1 receptor (IGF-1R) expression and subsequently impairing IL-10 in activated RA cells, contributes to the imbalance of proinflammatory and anti-inflammatory cytokines and pathogenesis of RA [16]. Serum miR-223 levels are shown to be a marker of disease activity and treatment outcome in patients with treatment-naïve early RA [7]. Shibuya et al. showed miR-223 expression in synovial tissue cells of superficial and sublining layers in RA patients in CD68+ macrophages, CD14+ monocytes, and CD4+ T cells and higher expression in RA compared to OA synovial cells. miR-223 overexpression was shown to suppress osteoclastogenesis, and nuclear factor I-A (NFI-A) was considered as a target of miR-223 which was downregulated [39]. Li et al. subsequently confirmed higher miR-223 expression in RA synovium and CIA joints compared to OA tissues but paradoxically showed that silencing of this miRNA results in

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reduced osteoclastogenesis and bone resorption by increasing NFI-A levels [40] (Table 5). miR-323p miR-323-3p is reported to be significantly upregulated in RA synovial fibroblasts enhancing Wnt pathway partly due to abnormal expression of β-transducin repeat containing (BTRC) in RA SF [37]. Higher Wnt expression has also been reported in RA synovium, and this signaling pathway is critically involved in FLS activation, bone resorption, and joint destruction during RA development [44]. Therefore, miR323-3p inhibitors may have therapeutic value in RA (Table 5). miR-346 miR-346 is shown to be able to cause the inhibition of IL-18 release through the indirect inhibition of Bruton’s tyrosine kinase gene transcription and IL-18 mRNA degradation [41]. It also controls the release of TNF-α by stabilization of tristetraprolin (TTP) acting as an anti-inflamatory agent [42] (Table 5). miR-363 miR-363 has been reported to be significantly decreased in RASF and peripheral blood CD4+ T cells compared to normal peripheral blood CD4+ T cells [20] (Table 5). miR-451 miR-451 was found to be overexpressed in T cells of patients treated with MTX and also newly diagnosed, disease modifying anti-rheumatic drug-free RA patients, and miR-451 expression in T cells was positively associated with disease activity score, erythrocyte sedimentation rate (ESR), and serum levels of IL-6 [28]. In neutrophils of RA patients, miR-451 is reported to be significantly lower compared to HC and the decrease might be in response to cytokine stimulus. It was revealed that miR-451 has a suppressive role in neutrophil chemotaxis via p38 MAPK and its downregulation might be responsible for deregulated neutrophil migration and disease deterioration. Furthermore, miR-451 downregulated IL-6 production from FLS via Rab5a and CPNE3, playing major role in inflammation in RA. Intravenous administration of miR451 reduced the severity of arthritis in mouse models implying a potential therapeutic role for this miRNA [43]. miR-498 miR-498 is shown to be downregulated in RA CD4+ T cells with no correlation to cytokine levels [20].

Increased

Increased

Increased

Increased

RA and OA synovial macrophages and monocytes

PBMC of RA and OA patients and HC

RA and HC PBMC and FLS

Sera of treatment-naïve early RA patients, established treated RA patients, and HC

-Higher expression in RA PBMC compared to HC -Highly expressed in patients with severe joint destruction and high disease activity -Significant upregulation in the RA synovial compartment, CD68+ macrophages in the membrane lining layer, and in synovial CD14+ cells -Associated with the lower expression of SHIP-1 in CD14+ cells and in macrophages in RA synovial tissue -Increased proinflammatory cytokines (IL-6 and TNF-α) -Higher miR-155 expression in RA compared to OA and HC -Positive correlation of miR-155 and TNF-α and IL-1β production in PBMC -Higher expression in RA PBMC compared to HC -Positive correlation with CRP -Upregulation after TNF-α stimulation -Inverse correlation with MMP-3 levels -Upregulation caused inhibition of RA FLS proliferation -Transfection suppressed RA FLS invasion -Higher levels in established RA compared to early RA and HC

-Increased expression of miR-155 compared to healthy and disease controls -1.6-fold increased expression in monocyte/macrophages compared to lymphocytes -Overexpression in RASF and tissue compared to OA synovium -Upregulation after proinflammatory mediator stimulation (TNF-α, IL-1-β and TLR ligands) -MMP-3 downregulation -Blocking the induction of MMP-1 and MMP-3 by cytokines Higher in RA compared to OA

Notes

Long et al. [31]

Filková et al. [7]

–

Li et al. [32]

Suppression of SOCS1 and thus upregulation of TNF-α and IL-1β IKBKE

Kurowska-Stolarska et al. [30]

Murata et al. [6] Niimoto et al. [4]

– – SHIP-1

Stanczyk et al. [26]

Pauley et al. [5]

–

MMP-3, MMP-1

Reference

Targets

CRP C reactive protein; FLS fibroblast-like synoviocytes; HC healthy controls; MMP matrix metalloproteinase; OA osteoarthritis; PBMC peripheral blood mononuclear cells; RA rheumatoid arthritis; RASF RA synovial fibroblasts; SHIP-1 Src homology 2-containing inositol phosphatase; SOCS1 suppressor of cytokine signaling 1; TLR Toll-like receptor; TNF-α tumor necrosis factor alpha

Increased Increased

Increased

RA and OA synovial fibroblasts, synovial tissues, and monocytes

OA and RA synovial fluid

Increased

PBMC of RA patients and healthy and disease controls

PBMC and synovium of RA and OA patients

Changes

Researches on miR-155 in RA

Tissue or cell line

Table 4

Clin Rheumatol (2015) 34:615–628 623

Increased

Increased

SF from RA and OA patients

RA and OA synovial fluid and plasma

RA and HC peripheral blood CD3+ lymphocytes

miR-221/222

miR-223

LPS-activated RA FLS

Overexpression

Human PBMC/RASF coculture system CIA mouse model

miR-346

Increased

RA and OA synovium

RA and OA SF

Transfection No change

Jurkat cells Sera of treatment-naïve early RA, established treated RA patients, and HC

miR- 323-3p

Increased

Increased

Overexpressed

Silencing

Increased

RA and OA FLS

RA and HC T cells

Overexpressed

Increased

SF from RA and OA patients

miR-203

Changes

Tissue or cell line

-Overexpression in RA T cells compared to normal T cells -Positive correlation with RF titer -Microarray of predicted targets showed decreased CSPG5 mRNA expression -Decreased IGF-1-mediated IL-10 production -No difference between the three groups -Positive correlation with CRP and disease activity in early RA patients -Significant decrease in early RA patients after 12 months of treatment compared to baseline -Increased in RA synovium compared to OA -miR-223 high expression level associated with poorly controlled and acute severe synovitis and bone destruction -miR-223 acted on PBMC in the coculture system -Downregulation of osteoclastogenesis marker genes -Increased miR-223 expression in synovial tissue of RA patients and ankle joints of mice with CIA compared to OA -Improvement in clinical signs of CIA by miR-223 silencing -Reduction in osteoclastogenesis and bone erosion -Positive regulator of Wnt/cadherin signaling in RA SF -Indirectly inhibits Btk and suppresses IL-18 release from LPS-activated RA FLS

-In RA and OA, higher concentrations in plasma compared to synovial fluid -Higher concentrations in synovial fluid and plasma of RA compared to OA -Inverse correlation with disease activity and number of tender joints -Unexpectedly overexpressed in naive CD4+ T cells -Barely detectable in Th17 cells -No miR-223 expression in HC naive CD4+ T cells even after TCR stimulation -No correlation with disease activity and severity -Stronger expression in RA FLS than OA FLS

-Upregulation in RA compared to OA -Overexpression results in increased IL-6 and MMP-1 production and joint destruction -Overexpressed in RASF compared to OA

Notes

Researches on miR-203, miR-221/222, 223, 323-3p, 346, 363, 451, and 498 in RA

miRNA

Table 5

Murata et al. [6]

Fulci et al. [38]

Nakamachi et al. [2]

–

–

–

Shibuya et al. [39]

–

Pandis et al. [37]

Wnt and cadherin signaling, BTRC expression Btk

Alsaleh et al. [41]

Li et al. [40]

NF-1A

Downregulation of NFI-A

Filková et al. [7]

IGF-1R and IL-10 –

Lu et al. [16]

Pandis et al. [37]

–

CSPG5

Stanczyk et al. [36]

Reference

IL-6 (indirect target) and MMP-1

Targets

624 Clin Rheumatol (2015) 34:615–628

Transfection Transfection

Increased

HeLa cells

RA FLS

RA and HC naïve and memory T and Treg cells -Downregulated in RA synovial fluid CD4+ T cells -No correlation with cytokine levels

-Transfection with miR-451 or 14-3-3ζ siRNA or Rab5a siRNA downregulated phosphorylation of p38 MAPK -miR-451 transfection significantly decreased 14-3-3ζ, Rab5a, and CPNE3 mRNA -14-3-3ζ siRNA transfection increased IL-6 -Rab5a siRNA and miR-451 transfection decreased IL-6 production -Positive correlation with disease activity, ESR, and IL-6

-miR-346 overexpression in LPS-stimulated FLS and not THP-1 cells -Controls the expression of TNF-α by regulating TTP expression in activated RA FLS and THP-1 cells -Downregulated in RA -No correlation with cytokine levels -Decreased expression in RA neutrophils compared to HC -miR-451 suppressed neutrophil chemotaxis to inflammation site -Downregulation of CPNE3 and Rab5a

Notes

Li et al. [20] Murata et al. [43]

– –

Smigielska-Czepiel et al. [28] Li et al. [20]

– –

14-3-3ζ, Rab5a, and CPNE3

CPNE3 and Rab5a transcription and translation 14-3-3ζ and Rab5a

–

Semaan et al. [42]

Reference

TTP, TNF-α

Targets

Btk Bruton’s tyrosine kinase; BTRC β-transducin repeat containing; CIA collagen-induced arthritis; ESR erythrocyte sedimentation rate; FLS fibroblast-like synoviocytes; HC healthy controls; IGF-1 insulin-like growth factor-1; LPS lipopolysaccharide; MMP matrix metalloproteinase; NF1-A nuclear factor 1A; OA osteoarthritis; PBMC peripheral blood mononuclear cells; RA rheumatoid arthritis; RF rheumatoid factor; SF synovial fibroblasts; siRNA small interfering RNA; TCR T cell receptor; Th T helper; TNF-α tumor necrosis factor alpha; Treg regulatory T cells; TTP tristetraprolin

Decreased

Overexpression

HeLa cells

CD4+ T cells of RA patients and HC

Overexpression

Mice models

miR-498

Decreased

RA and HC neutrophils

miR-451

Decreased

Increased

RA FLS and THP-1 cells in response to LPS

CD4+ T cells of RA patients

Changes

Tissue or cell line

miR-363

miRNA

Table 5 (continued)

Clin Rheumatol (2015) 34:615–628 625

626

Discussion ACPA and rheumatoid factor (RF) have long been used as biomarkers for RA, but there are patients in whom these factors are negative. New biomarkers which can help to diagnose the disease early, predict its course, and the therapeutic effects of different medications with high sensitivity and specificity are of great importance. Recently, miRNAs in body fluids are increasingly used as diagnostic and prognostic biomarkers in different disease states. They are rather stable in the blood even at room temperature and after freeze-thaw cycles and are tissue specific showing detectable alterations in different disorders. miRNAs can be reliably measured in various sources such as blood, biological fluids, tissue sample, and even formalin-fixed paraffin-embedded samples [45]. A study has shown the high degree of correlation of whole blood and PBMC miR-146a and miR-155 in RA and HC, proposing that whole blood can appropriately be used to investigate miRNAs [46]. miR-16 and miR-146 were 2 miRNAs indicating a correlation with RA active state in patients [5]. Plasma miR-132 has been proposed as a diagnostic marker for differentiating patients with RA and OA from HC. However, miR-132 was not able to differentiate RA patients from OA [6]. miR-24 and miR-125a-5p are considered as inflammatory miRNAs, concurrently used for diagnosis of RA [14]. Plasma levels of miR-16, miR-146a, miR-155, and miR-223 are correlated with disease activity and can serve as biomarkers for treatment efficacy evaluation and patients’ follow-ups [6]. miR-124a is also downregulated in RA, and this causes cell proliferation so it may be an appropriate candidate for application as RA treatment via gene-transfer systems to the affected joints [47]. Nakamachi et al. in 2015 have shown these potential therapeutic effects of miR-124a on RA by targeting RANKL and nuclear factor of activated T cell cytoplasmic 1 (NFATc1) [48]. miR-223 is upregulated in RA and is expressed in macrophages, monocytes, and T cells which are responsible for joint destruction. Shibuya et al. suggested that miR-223 administration can be considered as a promising treatment for bone destruction by suppression of osteoclastogenesis in the pannus of RA patients [39]. On the other hand, Li et al. proposed that miR-223 silencing can ameliorate experimental arthritis by increasing NF-1A levels and decreasing M-CSFR levels [40]. miR-23b can also be regarded as a therapeutic target with anti-inflammatory effects. It is downregulated in RA, inversely correlated with IL-17, and its transfection has been discovered to have autologous therapeutic effects on degenerative courses in RA and OA [12, 13]. Intravenous miR-451 has been shown to improve arthritis in mice models implying the potential therapeutic role of miR-

Clin Rheumatol (2015) 34:615–628

451 in RA. It is implicated that downregulation of this miRNA leads to dysregulation of cell infiltration and exacerbation of the disease [43]. miR-17∼92 cluster by targeting ASK1 also seems to be a candidate in treatment of RA. ASK is reported to be a principal factor in the development of RA and joint injury induced by TNF-α and other inflammatory mediators [1]. miRNAs can also serve as biomarkers for treatment efficacy. miR-125b has been proposed as a biomarker for predicting the response to rituximab therapy [19].

Conclusion The miRNA network is increasingly investigated in the pathogenesis of autoimmune diseases, and more studies are unraveling the targets and networks involved in the diseases such as RA. miRNAs in different forms—in clusters or star forms—are attractive targets as biomarkers or therapeutic candidates in order to improve the outcome of RA.

Conflict of interest None

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