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MicroRNA-Mediated Epigenetic Regulation of Rheumatoid Arthritis Susceptibility and Pathogenesis.

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Affiliations

  • 1. Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
      Authors
    • Chang C 1
    • Xu L 1
    • Jin Y 1
    • Jiang P 1
    • Wei K 1
    • Xu L 1
    • Shi Y 1
    • Zhao J 1
    • He D 1
    (9 authors)
  • 2. The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
      Authors
    • Zhang R 2
    (1 author)
  • 3. Department of Biostatistics and Data Science, School of Public Health, University of Texas Health Science Center, Houston, TX, United States.
      Authors
    • Xiong M 3
    (1 author)
  • 4. Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI, United States.
      Authors
    • Guo S 4
    (1 author)

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Frontiers in Immunology, 24 Mar 2022, 13:838884
https://doi.org/10.3389/fimmu.2022.838884 PMID: 35401568 PMCID: PMC8987113

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Abstract 

MicroRNAs (miRNAs) play crucial roles in regulating the transcriptome and development of rheumatoid arthritis (RA). Currently, a comprehensive map illustrating how miRNAs regulate transcripts, pathways, immune system differentiation, and their interactions with terminal cells such as fibroblast-like synoviocytes (FLS), immune-cells, osteoblasts, and osteoclasts are still laking. In this review, we summarize the roles of miRNAs in the susceptibility, pathogenesis, diagnosis, therapeutic intervention, and prognosis of RA. Numerous miRNAs are abnormally expressed in cells involved in RA and regulate target genes and pathways, including NF-κB, Fas-FasL, JAK-STAT, and mTOR pathways. We outline how functional genetic variants of miR-499 and miR-146a partly explain susceptibility to RA. By regulating gene expression, miRNAs affect T cell differentiation into diverse cell types, including Th17 and Treg cells, thus constituting promising gene therapy targets to modulate the immune system in RA. We summarize the diagnostic and prognostic potential of blood-circulating and cell-free miRNAs, highlighting the opportunity to combine these miRNAs with antibodies to cyclic citrullinated peptide (ACCP) to allow accurate diagnosis and prognosis, particularly for seronegative patients. Furthermore, we review the evidence implicating miRNAs as promising biomarkers of efficiency and response of, and resistance to, disease-modifying anti-rheumatic drugs and immunotherapy. Finally, we discuss the autotherapeutic effect of miRNA intervention as a step toward the development of miRNA-based anti-RA drugs. Collectively, the current evidence supports miRNAs as interesting targets to better understand the pathogenetic mechanisms of RA and design more efficient therapeutic interventions.

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Front Immunol. 2022; 13: 838884.
Published online 2022 Mar 24. https://doi.org/10.3389/fimmu.2022.838884
PMCID: PMC8987113
PMID: 35401568

MicroRNA-Mediated Epigenetic Regulation of Rheumatoid Arthritis Susceptibility and Pathogenesis

Cen Chang, 1 , 2 , † Lingxia Xu, 1 , 2 , † Runrun Zhang, 3 Yehua Jin, 1 , 2 Ping Jiang, 1 , 2 Kai Wei, 1 , 2 Linshuai Xu, 1 , 2 Yiming Shi, 1 , 2 Jianan Zhao, 1 , 2 Momiao Xiong, 4 Shicheng Guo,corresponding author 5 , 6 , * and Dongyi Hecorresponding author 1 , 2 , 7 , *
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Abstract

MicroRNAs (miRNAs) play crucial roles in regulating the transcriptome and development of rheumatoid arthritis (RA). Currently, a comprehensive map illustrating how miRNAs regulate transcripts, pathways, immune system differentiation, and their interactions with terminal cells such as fibroblast-like synoviocytes (FLS), immune-cells, osteoblasts, and osteoclasts are still laking. In this review, we summarize the roles of miRNAs in the susceptibility, pathogenesis, diagnosis, therapeutic intervention, and prognosis of RA. Numerous miRNAs are abnormally expressed in cells involved in RA and regulate target genes and pathways, including NF-κB, Fas-FasL, JAK-STAT, and mTOR pathways. We outline how functional genetic variants of miR-499 and miR-146a partly explain susceptibility to RA. By regulating gene expression, miRNAs affect T cell differentiation into diverse cell types, including Th17 and Treg cells, thus constituting promising gene therapy targets to modulate the immune system in RA. We summarize the diagnostic and prognostic potential of blood-circulating and cell-free miRNAs, highlighting the opportunity to combine these miRNAs with antibodies to cyclic citrullinated peptide (ACCP) to allow accurate diagnosis and prognosis, particularly for seronegative patients. Furthermore, we review the evidence implicating miRNAs as promising biomarkers of efficiency and response of, and resistance to, disease-modifying anti-rheumatic drugs and immunotherapy. Finally, we discuss the autotherapeutic effect of miRNA intervention as a step toward the development of miRNA-based anti-RA drugs. Collectively, the current evidence supports miRNAs as interesting targets to better understand the pathogenetic mechanisms of RA and design more efficient therapeutic interventions.

Keywords: rheumatoid arthritis, microRNA, susceptibility, pathogenesis, epigenetics

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic joint inflammation and structural damage, accompanied by extra-articular manifestations such as rheumatoid nodules, interstitial pneumonia, vasculitis, and systemic complications. RA is typically progressive and insidious, with an incidence rate of 0.5–1% in Europe and North America (1). However, the precise mechanisms underlying the pathogenesis, disease activity, and severity of RA as well as the causes of different response to treatment are not fully understood. In view of current therapy strategies and treatment frames, early accurate diagnosis, effective and personalized treatment, and precision medicine have become increasingly urgent for patients with RA. A comprehensive understanding of RA is required from the perspectives of both genetics (2) [human leukocyte antigen (HLA) and non-HLA variants] and epigenetics [DNA methylation (3–5), microRNA (6), long non-coding RNA (7, 8), and histone modifications (9)].

MicroRNAs (miRNAs) are small endogenous non-coding RNAs with a length of around 22 nucleotides, and are involved in the post-transcriptional regulation of gene expression. In recent years, accumulating studies have demonstrated that miRNAs play a key role in various cancers (10–14) and autoimmune diseases, including RA, systemic lupus erythematosus (15, 16), Sjögren’s syndrome (17), and systemic sclerosis (18). In this review, we systematically summarize recent advances in understanding the role of miRNAs in RA. Emphasize the important role of miRNA in RA susceptibility, pathogenesis, and efficacy evaluation. Provide evidence supporting precision medicine research in RA.

Genetic Variations in miRNAs Explains Susceptibility of RA

Genome-wide association studies have identified >100 genetic factors for RA. However, these genetic variants only explain < 40% of the overall heritability of RA, and thus most of the heritability has not been explained, suggesting the need for more studies using different approaches and populations to identify the missing causes. Association studies of miRNA loci can reveal RA-associated functional or causal variants within different populations, such as Chinese (19, 20), Egyptian (21–23), Polish (24), Mexican (25), and Iranian (26) subjects. Gene expression and genetic polymorphisms of miR-146a and miR-499 showed diagnostic potential for RA (23). Consistently, the polymorphism rs3027898 in IRAK1, the target gene of miR-146a, is linked to RA in the Greek population (27). In contrast, miR-146a rs2431697 is associated with RA susceptibility in Chinese population (28). The rs3746444 (20q11.22, A>G) polymorphism of miR-499, which is encoded by the intron of MYH7B, is significantly linked to RA risk, disease activity, and methotrexate (MTX) toxicity. Interestingly, the AA genotype shows higher disease activity and MTX toxicity than the AG/GG genotypes (29). The AA and AG genotypes in the miRNA binding site rs3135500 of NOD2 are significantly associated with the risk of RA, with rs3135500 (A allele) showing a significant relationship with increased erythrocyte sedimentation rates (ESR) and C-reactive protein (CRP) concentrations (30). However, some studies showed inconsistent results in Polish (24), Mexican (25), and Chinese (19, 20, 31, 32) populations, suggesting that genetic polymorphisms of miR-146a and miR-499 are not significantly associated with RA susceptibility. For example, miR-499 rs3746444 A/G are not significantly associated with RA in Mexican people (25). miR-146a rs2910164 (20, 32) and miR-499 rs3746444 (20, 31) do not significantly correlate with RA in Chinese people. However, in addition to race, factors of individual heterogeneity and sample size should also be considered while evaluating inconsistent results. Moreover, the sample size of the above studies was not large. We recently demonstrated that meta-analysis could identify more significant single-nucleotide polymorphisms in a large sample size, and found that the interaction between HLA alleles and miRNA single-nucleotide polymorphisms (such as rs5997893 in miR-3928 and rs4947332 in HLA-DRB1) should be considered to explain susceptibility (33). In summary, genetic variations in miRNAs can help to explain the susceptibility to RA.

Regulatory Roles of miRNAs in Cells and Their Secretions Involved in RA Pathogenesis

Fibroblast-like synoviocytes (FLS) and immune cells are the main cell types involved in the pathogenesis of RA. These cells can secrete exosomes and other substances to affect the occurrence and development of RA. Current researches have mainly focused on understanding miRNA-mediated transcriptional regulation of FAF1 (34), TNF-α (35), STAT1 (36), STAT3 (37), and mTOR (38, 39). miRNAs regulate inflammation, immune response, proliferation, and differentiation. Meanwhile, miRNA influence the micro-environment within synovial joints by targeting target genes and their related pathways, including Fas-FasL (34) and the NF-κB (40, 41) pathways. In this section, we summarize the regulatory roles of miRNAs in the main RA-associated cell entities, focusing on FLS, immune cells, and exosomes to highlight the importance of miRNAs in the pathogenesis of RA.

Effects of miRNAs on FLS in RA

FLS in RA (RA-FLS) are key regulators of inflammation and bone destruction in RA. The aberrantly expression of miRNAs in RA-FLS play an important role in the pathogenesis of RA. For example, miR-625 is down-regulated in RA-FLS, which negatively impacts the expression of CTSC, KLF8, and EBF3. In contrast, miR-551b is up-regulated in RA-FLS, inhibiting the expression of ITGBL1 (42).

Dysregulation of miRNAs in RA-FLS affects biological functions such as cell proliferation, invasion, migration and apoptosis. Up-regulation of miR-145 affects all biological functions of RA-FLS by targeting SEMA3A (43). The expression of miR-29c-3p and miR-132-3p are decreased while miR-31-5p was increased in RA- FLS, and their dysregulation are associated with proliferation, invasion and migration of RA-FLS. Down-regulated miR-29c-3p promoted proliferation, invasion and migration of RA-FLS through up-regulation of COLA1 expression. Interestingly, up-regulated miR-31-5p and down-regulated miR-132-3p inhibited the proliferation, invasion and migration of RA-FLS by negatively regulating WASF3 and RB1, respectively, suggested that miR-31-5p and miR-132-3p are protective factors in RA (44). Down-regulation of miR-199a-3p (45), miR-449 (46), miR-431-5p (47), and up-regulation of miR-483-3p (48) can promote the proliferation and suppressed apoptosis by targeting RB1, HDAC1, XIAP, IGF-1, respectively. miR-124a is down-regulated and targets CDK2 and MCP-1 which only enhanced the proliferation of RA-FLS (49).

Dysregulation of miRNAs in RA-FLS can also affects the level of inflammation. Down-regulation of miR-126 (35), miR-23 (50) and up-regulation of miR-143 (43) can increase the release of inflammatory factors such as TNF-α, IL-1β, IL-6 through up-regulation of IL-23R, CXCL12 and down-regulation of IGFBP5 and thus affect the course of RA. What’s more, some miRNAs not only affects the level of inflammation, but also associated with biological functions of RA-FLS. For example, down-regulation of miR-137 (51) and miR-23a-5p (52) targeting LSD and TLR4 promotes proliferation, invasion, migration and inhibits apoptosis of RA-FLS and inhibits the release of inflammatory factors IL-1β and IL-6. Down-regulation of miR-29a (37) and miR-27a-3p (53) are associated with proliferation, apoptosis, and promoting secretion of TNF-α, IL-1, IL-6 and IL-8. Then, down-regulation of miR-22 (54), miR-124 (55) and miR-34a-5p (56) can enhanced proliferation of RA-FLS and the level of IL-6.

Additionally, the biological functions of RA-FLS and the level of inflammation are correlated with matrix metalloproteinases (MMPs) (57). Down-regulation of miR-203 (41, 42) and miR-147b-3p (58) increased the expression of MMP-1, MMP3 and MMP9, respectively, which in turn enhanced the expression of some inflammatory factors, such as IL-6 and TNF-α. Down-regulation of miR-27a (59) can contribute to MMPs gene expression by targeting the IL-17 pathways, thereby affecting the proliferation and invasion of RA-FLS. Conversely, up-regulated miR-155 could be a protective factor by inhibiting proliferation and invasion while attenuating the expression of MMP3 and IKBKE (60, 61).

In addition, dysregulation of miRNAs in RA-FLS affects joint bone erosion through the release of inflammatory cytokines, chemokines and MMPs, which may be an option for RA treatment (62, 63). For example, up-regulated miR-145-5p (40) and down-regulated miR-17-5p (64) affect bone and cartilage destruction through the release of IL-1β, IL-6, IL-8, MMP-1, MMP-3 and MMP-9. In vitro, overexpression of miR-221-3p inhibits osteoblast differentiation (65). Instead, miR-218 overexpression promotes osteogenic differentiation of RA-FLS by suppressing the Roundabout-1/Dickkopf-1 axis (66). miR-20a (67) and miR-21 (68) are targets of the TLR4/p38 and JAK/STAT3 signaling pathways respectively, affecting the proliferation and osteogenic differentiation of RA-FLS.

In summary, studies of miRNAs in RA-FLS have improved the understanding of the pathogenesis of RA. miRNAs are widely involved in the functions of FLS, and therefore are promising targets for drug development ( Figure 1 ).

An external file that holds a picture, illustration, etc. Object name is fimmu-13-838884-g001.jpg

Effects of dysregulation of the miRNA-mRNA network on RA-FLS. The dysregulation of miRNAs and their target mRNAs in RA-FLS affects the biological function (such as proliferation, invasion, migration, and apoptosis), inflammatory levels, and joint bone destruction. Inflammatory levels are mainly related to the release of inflammatory factors such as IL-8, IL-6, and joint bone destruction is mainly related to the release of MMPs. Dysregulation of different miRNA-mRNA combinations affects different processes in RA-FLS. Rounded rectangles represent miRNAs; rectangles represent target mRNAs; pink represents upregulation; blue represents downregulation.

Effects of miRNAs on Immune Cells in RA

miRNAs have recently emerged as key regulators of the immune system, being involved in lymphocyte selection and proliferation, in T(reg) cells differentiation. In peripheral blood mononuclear cells (PBMCs), decreased expression of miR-671 and miR-7 may correlate with the expression of CDR1 and mTOR (38). And miR-29b enhances the anti-apoptotic effect by inhibiting the high-mobility group box-containing protein 1 (HBP1) (69).

In T cells sub-population derived from PBMCs, miR-99b-5p down-regulates mTOR and RASSF4, thereby inhibiting T cell apoptosis and promoting T cell proliferation and inflammatory response (39). Besides, miR-146a, miR-26, miR-let-7a, miR-146b, miR-150, miR-155 are increased and miR-363, miR-498 are decreased in the CD4+ T cell sub-type in PBMCs, Among these miRNAs, miR-146a may affect the apoptosis of T cell and RA progression by targeting IL-17 and Fas associated factor 1 (FAF1) (34, 70). Interestingly, miR-233 is highly expressed only in naive CD4+ lymphocytes but not in T(h)-17 cells, suggesting the importance to investigate the impact of miRNA on the pathogenesis of RA at the single-cell level (71).

There are numerous of miRNAs are also associated with other T cells sub-types, such as Treg cells and Th17 cells. The balance of Th17/Treg cells plays a crucial role in RA. IL-17 released by Th17 up-regulates the expression of RANKL on synovial fibroblasts stimulating the production of inflammatory cytokines such as TNF-α, IL-1, and IL-6 (72). Decreased levels of miR-20a (73) and miR-21 (74, 75) exacerbate the RA process by stimulating the NLRP3 inflammasome pathway and increasing STAT3 expression, respectively, while decreasing STAT5 expression, all of which are associated with the imbalance of Th17/Treg cells. Although miR-210-mediated negative regulation of HIF-1 also affects the dynamic equilibrium of Th17/Treg cells. Regrettably, the levels of miR-210 between RA and healthy controls have no significant difference (76). Interestingly, the expression of miR-146a is decreased in Treg cells during high RA activity, leading to a proinflammatory phenotype in these cells caused by concomitant up-regulation of its target STAT1 (36). For instance, miR-21 and miR-155 are related to the memory phenotype, and miR-92a relative to the naïve phenotype (77).

Besides, in macrophages, binding of miR-6089 and lncRNA-HIX003209 enhances the expression of TLR4 and exacerbates inflammation via the TLR4/NF-κB pathway (78). Up-regulation of miR-33 induces the expression of NLRP3 and 73 (79). Overall, miRNAs cooperate with other non-coding RNAs to alter the DNA methylation and/or expression of their targets, thus regulating innate and adaptive immune cells differentiation and apoptosis, ultimately influencing the inflammatory and autoimmune response in RA ( Table 1 ).

Table 1

Effects of microRNAs on immune cells in rheumatoid arthritis.

miRNAmiRNA trendsTargetsTargets trendsLocationFunctionsReference
miR-671↓CDR1↑PBMC/ (40)
miR-7↓mTOR↑
miR-29b↑HBP1↑ (73)
miR-99b-5p↑mTOR↑T cellinhibiting T cell apoptosis, promoting T cell proliferation, inflammatory response (41)
RASSF4
miR-146a↑FAF1↑inhibiting apoptosis of T cell and RA progression (35)
IL-17↑ (74)
miR-26↑/// (35, 74)
miR-let-7a↑
miR-146b↑
miR-150↑
miR-155↑
miR-363↓
miR-498↓
miR-233↑ (75)
miR-20a↓NLRP3↑Treg/Th17the imbalance of Th17/Treg cells (77)
miR-21↓STAT3↑ (78, 79)
STAT5↓
miR-210↓HIF-1↑ (80)
miR-146a↓STAT1↑Treg cells/ (38)
miR-6089↓TLR4↑macrophagesexacerbates inflammation via the TLR4/NF-κB pathway (81)
miR-33↑NLRP3↑/ (82)
caspase-1

Effects of miRNAs on Cell Secretions in RA

Exosomes are secreted from cells and contain signal molecules such as miRNA, protein, and DNA, which have biological functions. Exosomal miRNA derived from bone marrow-derived mesenchymal stem cells has been shown to be closely related to the occurrence and development of RA. Among these exosomes, MSCs-drived miR-124a over-expression exosomes inhibit the proliferation and migration and promote the apoptosis of RA-FLS (80). Over-expression of miR-23b (83) and miR-34a (81) can inhibit the differentiation of Th17 cells, by reducing IL-17 secretion and targeting the cyclin I/ATM/ATR/p53 signaling pathway, respectively. Up-regulated of miR-21 (82) which targets TET1, reduce RA inflammation. Macrophage-derived exosomes miR-506-3p (84) and miR-103a (85) regulate the progression of RA by inhibiting the RANKL/NFATc1 signaling pathway and activating the JAK/STAT3 signaling pathway. miR-132 secreted by aryl hydrocarbon receptor activation Th17 in extracellular vesicles acts as a pro-inflammatory mediator to reduce the production of COX2, to increase the production of osteoclast (86). In addition, cell-derived small extracellular vesicles of miR-574-5p induces osteoclast differentiation by targeting TLR 7/8 (87), whereas miR-150-5p exosomes alleviates RA-FLS proliferation and angiogenesis and reduces RA joint destruction by targeting MMP14 and VEGF (88). Based on these results, miRNAs play an important role in the pathogenesis of RA and may represent promising outcome biomarkers and novel drug targets to decrease disease severity.

Blood and Serum-Circulating miRNAs Provide Novel Opportunities for Precision Medicine of RA

miRNAs as Potential Biomarkers for Early Prevention and Precision Diagnosis

Emerging evidence indicates the potential of blood-circulating miRNAs associated with RA as biomarkers for early prevention. The levels of miR-371b, miR-483, and miR-642b are significantly up-regulated, whereas miR-25 and miR-378d are down-regulated in PBMCs in individuals who eventually develop RA from early undifferentiated arthritis (89). Additionally, miR-22 (90), miR-361-5p (91), and miR-223-3p (91) are significantly up-regulated in high-risk or CCP-positive populations. All these miRNAs may therefore be useful biomarkers for the early diagnosis of RA. Expression of miR-103a-3p is significantly increased in autoantibody-positive, symptomatic first-degree relatives and patients with RA, suggesting it as a potential biomarker for predicting imminent disease in individuals at risk for developing RA (92). Additionally, higher level of miR-99b-5p is found in the plasma of patients with early RA who progress to bone erosion after 12 months, indicating that miR-99b-5 can be monitored for bone erosion surveillance in RA patients (93).

In addition to playing a role in the early prevention of RA, the expression of some miRNAs can aid in improving the accuracy of RA diagnosis (94). The expression of miR-146a and miR-155 are significantly increased in RA PBMCs and whole blood (95). The levels of miR-24 and miR-125a are significantly higher in the serum of patients with RA regardless of the CCP status (96). Interestingly, analysis of miR-24-3p, miR-26a-5p, and miR-125a-5p levels in combination are a better diagnostic tool for RA, even though these miRNAs are not related to disease activity (97). Furthermore, miR-122-3p, miR-3925-3p, miR-342-3p, and miR-4764-5p show differential expression not only between healthy individuals and RA patients, but also between patients with RA and patients with osteoarthritis, systemic lupus erythematosus, or Graves, which show great potential as biomarkers to distinguish RA patients from HC or other diseases (98). The serum levels of miR-146a (99, 100), miR-22-3p (101), miR-5571-3p (102), and miR-135b-5p (102) are significantly higher in RA patients than in healthy controls and osteoarthritis patients. Other differentially expressed miRNAs in patients with RA serum include miR-4634, miR-181d, miR-3926, miR-9-5p, miR-219-2-3p6, miR-221, miR-222, miR-532, miR-106a, and miR-98 highlighting their potential as RA-specific diagnostic markers (98, 103). Nevertheless, the above miRNAs should be selected as biomarkers with caution. Their sensitivity and specificity need to be taken into consideration because they were only compared with patients with osteoarthritis (OA) or healthy control, and rarely analyzed with patients with other inflammatory autoimmune diseases, such as ankylosing spondylitis. In addition, it should be determined if the miRNA as diagnostic markers are expressed differently in patients before the onset of clinical symptoms. The above studies were conducted after patients were confirmed with RA diagnosis. Thus, more robust sample studies are needed to validate these markers in early RA.

miRNAs as Potential Biomarkers for Disease Activity and Treatment Response

The expression of miR-451 in T cells is significantly increased, which is positively correlated with the levels of disease activity score 28 (DAS-28), ESR, and serum IL-6 in RA (77). The level of miR-146a is positively correlated with the level of ESR and DAS-28 (99), whereas miR-5571-3p (102) correlates with the level of ESR and CRP, and miR-135b-5p only correlate with CRP (102). These miRNAs may therefore be suitable markers of disease activity in patients with RA. Increased serum miR-194-5p level is associated with disease recurrence (104). Concentration of circulating miR-23b, which positively correlates with ESR, CRP, and DAS-28, is significantly up-regulated after appropriate treatment, indicating that miR-23b is a dual marker for disease activity and prognosis (105). Similarly, miR-96-5p, miR-134-5p, miR-140-3p, miR-627-5p, miR-224, miR-760, miR-483-5p, miR-378, and miR-375 are not only diagnostic markers for RA, but also mirror disease activity (106, 107). However, these studies are still descriptive. Therefore, the underlying pathophysiology needs to be validated using other techniques.

Common and widely used anti-rheumatic drugs include cDMARDs (MTX, sulfasalazine, and hydroxychloroquine), bDMARDs (TNF-α inhibitors, rituximab, and tocilizumab), tsDMARDs (tofacitinib, barretinib, and filgotinib). Several studies have explored the relationship between serum miRNA levels and drug response. Evidence shows that high serum levels of miR-10 in patients with RA is correlated with good response to MTX (108). After 3 months of adalimumab/MTX combined treatment, the level of miR-27a-3p significantly decreased and clinical symptoms significantly improved (109). The reduced serum level of miR-5196 is positively correlated with the delta DAS28 after anti-TNF-α therapy (110). The level of miR-146a is increased in RA patients who respond well to anti-TNF therapy and, interestingly, can be considered as predictors of the response to anti-TNFα therapy together with CRP (24, 111, 112). In contrast, the serum levels of miR-23 and miR-223 are increased in patients with RA who respond well to anti-TNF-α/DMARD combination therapy, but correlate negatively with the response to anti-TNF drugs (111). High serum level of miR-125b is an indicator for good clinical response to rituximab therapy (113). Notably, miR-432-5p is significantly down-regulated in RA patients who are responsive to tofacitinib therapy but up-regulated in patients showing RA relapse (104). In RA, treatment with rituximab increases the levels of miR-16-5p and miR-23a-3p in the peripheral blood (114). The expression of miR-550b-2-5p, miR-4797-5p, miR-6509-5p, miR-378g, miR-4720-5p, miR-374b-5p, and miR-185-3p are different between individuals who show good vs poor responses to treatment with tripterygium glycosides (115, 116). Finally, the expression of miR-124a in FLS is increased following geniposide treatment; however, the relevance of this finding has not been assessed in clinical response studies (117).

In addition to DMARD treatment, alternative and complementary medicine preparations and mesenchymal stem cell treatments are also used in clinical practice. The auto-therapeutic effect of miRNAs has been demonstrated in mouse models of RA-FLS and autoimmune arthritis. For example, miR-449a mimics also inhibit the proliferation, migration, and IL-6 production of RA-FLS by regulating HMGB1 and YY1 expression (118). In the rat model with collagen-induced arthritis, miR-708-5p mimic improved pathological changes by inhibiting inflammatory cell infiltration, synovial hyperplasia, and cartilage destruction (119). An miR-126 agonist inhibits the expression of IL-23R, TNF-α, and IFN-γ in FLS (35). Furthermore, miR-26b-5p, miR-487b-3p, and miR-495-3p are significantly up-regulated in responders to adipose-derived mesenchymal stem cell treatment (120).

In summary, the changes of circulation miRNA in RA provide a promising opportunity for standard treatment, as well as indicate disease activity and predict RA outcomes.

miRNAs Research in RA: Remaining Challenges and Future Opportunities

In conclusion, miRNAs play multiple roles in the development of RA, from susceptibility to pathogenesis. Blood and serum-circulating miRNAs have been explored as important biomarkers for early diagnosis, prognosis, and drug response prediction. Furthermore, miRNAs have been proposed for autotherapeutic approaches and as novel drug targets for the treatment of RA. Genetic variants in specific miRNAs can increase or decrease the risk and disease activity of RA in various racial. Meanwhile they are associated with methotrexate toxicity and responses to other treatments. Moreover, changes in miRNAs in various cells are related to the pathogenesis of RA, such as the proliferation and differentiation of immune cells, proliferation and apoptosis of synovial cells, and synovial inflammation and cartilage destruction. Research has remarkably progressed towards the development of miRNAs as biomarkers in the diagnosis, prognosis, disease activity, and response to therapeutic drugs with RA, providing a direction for early diagnosis and accurate treatment of RA, to achieve better treatment efficiency and precision medicine. Numerous miRNAs have been shown to act as therapeutic targets in RA-FLS and collagen-induced arthritis rat models. Furthermore, miRNAs show potential for identifying the subtypes of RA. For example, the levels of miR-7 and miR-214-5p are significantly increased in the serum of patients with RA associated-interstitial lung disease (121), and miR-9-5p targets the REST/miR-132 pathway to protect Schwann cells from inflammatory damage in RA-induced peripheral neuropathy (122). Although we have reached exciting milestones in the research on the multiple roles of miRNA in RA, further studies should be performed to translate this knowledge for clinical applications and resolve the current inconsistent results among different studies employing different methods or populations. For example, studies of miR-99, miR-143, and miR-197 as landmark miRNAs for predicting the response to anti-TNF-α therapy have failed to yield consistent results (123). Finally, future development of miRNA-based baseline RA polygenetic risk score models, particularly in conjunction with HLA, is needed. miRNA-based early diagnosis, prognosis, and drug response prediction models can be applied in the clinic. With the identification of additional miRNAs-based drug targets in clinical research, miRNA-based autotherapeutic treatments may show more promising results.

Author Contributions

SG and DH conceived the content. CC and LXX wrote the manuscript. RZ, YJ, PJ, KW, and MX edited the manuscript. YS, JZ and LSX checked the manuscript information. LXX wrote the manuscript and LSX checked the manuscript information.

Funding

This work was funded by the National Natural Science Funds of China (82074234 and 82004166); Shanghai Chinese Medicine Development Office, National Administration of Traditional Chinese Medicine, Regional Chinese Medicine (Specialist) Diagnosis and Treatment Center Construction Project-Rheumatology; State Administration of Traditional Chinese Medicine, National TCM Evidence-Based Medicine Research and Construction Project, Basic TCM Evidence-Based Capacity Development Program; Shanghai Municipal Health Commission, East China Region based Chinese and Western Medicine Joint Disease Specialist Alliance.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

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