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MiRNAs in Rheumatoid Arthritis
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Rheumatoid arthritis (RA) is a heterogeneous disease where a specific immunologic and genetic/epigenetic background is responsible for disease manifestations and course.

rheumatoid arthritis (RA) immune and inflammatory responses bone destruction

1. Introduction

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory autoimmune disease that affects 1% of the population worldwide [1]. RA is a molecularly heterogeneous, complex, multifactorial disease with different biological and clinical characteristics. The chronic inflammatory process and autoimmunity associated with the disease mostly affect the synovium, which leads to joint damage and synovitis through the infiltration of inflammatory cells into the tissues [2]. A number of etiological factors associated with RA have been identified as hereditary, genetic, environmental and lifestyle factors. Epigenetic mechanisms may serve as a dynamic link between environment, genotype and phenotype. Accumulating evidence has demonstrated that aberrant epigenetic modification plays a pivotal role in triggering the dysregulation of T cell activation, leading to the incidence of RA [3][4][5]. Within the epigenetic factors participating in RA, micro-RNAs (miRNAs), playing an important role in many biological processes, are considered to be potential therapeutic targets for many autoimmune/inflammatory diseases, including RA [6][7]. Altered miRNA expression has been associated with the enhanced secretion of proinflammatory cytokines and increased numbers of inflammatory signaling pathways, as well as other processes that maintain the vicious cycle of autoimmunity [8]. Moreover, miRNAs also show immense potential for not only diagnostic (circulating miRNAs in serum are attractive biomarkers) but also therapeutic applications.
The treatment of RA is still a significant clinical challenge. Traditional treatments for RA involve suppressing the excessive immune and inflammatory responses, which may only help to relieve the symptoms of RA and delay the progression of the disease, not cure it. Moreover, these strategies lead to several systemic side effects. The therapy of RA is carried out based on targeted synthetic disease-modifying antirheumatic drugs (DMARDs), glucocorticoids and conventional synthetic DMARDs (csDMARDs), as well as biological DMARDs (bDMARDS). The csDMARDs used in RA treatment include methotrexate (MTX), hydroxychloroquine, sulfasalazine and leflunomide. MTX is the first choice regardless of disease activity [9], despite the fact that the ACR guidelines favor hydroxychloroquine and sulfasalazine over MTX for patients with lower disease activity to reduce the negative effects of MTX [10][11]. At the present time, among the bDMARDs used in the treatment of RA, we can distinguish anti-TNF drugs (such as etanercept (ETA), adalimumab (ADA), infliximab (IFX), certolizumab pegol, golimumab (GOL)), and TNF inhibitors are commonly used in the standard treatment of RA, mainly for patients in whom MTX treatment was unsuccessful. Around 80% of RA patients receive mixed therapy with MTX and TNF inhibitors [12][13]. Next, treatments use IL-6 receptor antagonists (tocilizumab (TCZ), sarilumab) and recombinant IL-1R blockers (anakinra). TCZ and sarilumab bind to the transmembrane IL-6 receptor, blocking the signaling of IL-6 [14]. Recent clinical trials show that sarilumab is more efficient in RA patients who do not respond well to MTX or TNF inhibitors [15]. Janus kinase (JAK) inhibitors are another group of inhibitors that are used in the treatment of RA. JAK is a receptor-associated tyrosine kinase whose role is to intervene in signals starting from inside a cell through transcription factors, such as STAT [16]. The JAK family consists of JAK1, JAK2, JAK3 and tyrosine kinase 2 (Tyk2). Baricitinib and tofacitinib are drugs already used in the treatment of RA. Additionally, they are JAK inhibitors. Baricitinib selectively inhibits JAK1 and JAK2, whereas tofacitinib inhibits JAK1, JAK2, JAK3 and Tyk2 [17][18]. Clinical trials show baricitinib presented an improvement of RA symptoms for subjects who did not respond well towards MTX, TNF inhibitors or csDMARDs [19][20][21]. A new strategy of treatment for RA should consist of the co-stimulation of T cell blockers using abatacept, which is an anti-CD80/86 inhibitor, B cell depletion drugs, such as rituximab, which is a chimeric anti-CD20 mAb, and JAK, using tofacitinib or baricitinib, which belong to the targeted synthetic DMARDS (tsDMARDs) [22][23][24][25][26].
Therefore, research investigating the effective molecular targets for treating RA is underway. The next, very important step in the near future will be to utilize miRNA as a novel therapy for RA. Various miRNAs related to inflammatory cytokines, osteoclast differentiation and synovial cell proliferation have been investigated for possible application in RA treatment [27]. Noting the importance of novel therapies, researchers focus on looking for reliable predictive biomarkers for better prognosis and therapeutic responses [28]. Researchers hope that miRNA will facilitate faster disease detection and better and more precise therapy.

2. Characteristics and Pathology of Rheumatoid Arthritis (RA)

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory autoimmune disease. The most frequent symptoms of RA are pain, stiffness and tenderness of joints, which lead to systemic complications, progressive disability and even early death. Current treatment relies on aggressive therapy immediately following diagnosis, with the pursuit of clinical remission by increasing therapy, depending on disease activity [1]. The main characteristics of RA are synovial hyperplasia and inflammation, the deformity of cartilage and bone, the production of anti-citrullinated protein antibodies (ACPA) or rheumatoid factors (RF), which are autoantibodies typical for RA, and systemic features, such as skeletal, pulmonary, cardiovascular and psychological disorders [29]. Additionally, RA rarely goes into total remission, and requires ongoing pharmacological therapy [9][30][31][32].
In RA, inflammation leads to bone destruction, cartilage degradation and synovial inflammation. Bone destruction is characterized by a disruption in bone formation. Macrophages activated by CD4 T Helper cells (Th cells) produce proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1 and IL-6, which activate osteoclastogenesis. These cytokines also activate the production of macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa B ligand (RANKL) from synovial joint cells, and activate RANKL on osteoblast cells to bind with receptor RANK on osteoclast precursor cells for osteoclast maturation [33]. In contrast, osteoclastogenesis is inhibited by osteoprotegerin, which blocks the osteoclast differentiation pathway by inactivating RANKL. In consequence, mature osteoclasts are responsible for the degradation of osteonectin and aggrecan, causing chronic joint destruction [34].
Proinflammatory cytokines, such as TNF-α, IL-1 and IL-6, are also responsible for stimulating synovial fibroblast cells to emit the cartilage-degrading enzymes, matrix metalloproteinases (MMPs). These enzymes are specific biomarkers for cartilage destruction in RA [35]. MMPs are inhibited and downregulated by tissue inhibitors of metalloproteinases (TIMPs), so the balance of MMPs and TIMPs in cartilage metabolism is important to maintain homeostasis [36]. Synovium is a primary area for inflammation, where a disturbance in immune tolerance leads to RA. Granulated macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), IL-6, IL-1β and IL-17 are the cytokines that have a key role in synovial inflammation and the activation of synovial mononuclear cells. Pannus is part of a synovial membrane made of granular tissues that is abundant with osteoclast. Free-roaming cartilage fragments and bone osteophytes in the synovial cavity are primary significant factors in synovial inflammation [37]. In pannus can be found Th cells, which are made up of the Th1, Th2 and Th17 cell subsets, and regulatory T cells (Treg) (Figure 1) [31].
Figure 1. The pathology of rheumatoid arthritis (RA), showing the process of cartilage and bone destruction. RA is distinguished by the formation of pannus, which is an abnormal layer of tissue created over the joint surface, leading to the erosion of articular cartilage and bone. Pannus contains macrophages, which create inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1 and IL-6, activating osteoclasts and resulting in bone destruction. Additionally, present in pannus are T cells, consisting of regulatory T cells (Treg) and T helper cells (Th), which are made up of the Th1, Th2 and Th17 cell subsets. Th17 cells are differentiated from naive T cells by IL-1β, IL-6, IL-21 and TGF-β. Th17 cells create IL-17, which acts on various immune cells to activate inflammation, and induces RANKL in synovial fibroblasts to activate osteoclasts. Th1 cells create IFN-γ, Th2 cells create IL-4 and Treg cells create CTLA-4, which are responsible for regulating osteoclast differentiation. Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), which are created by chondrocytes, synovial fibroblasts and synovial macrophages, lead to cartilage destruction.
Th cells are responsible for initiating the immune response, and Treg cells are responsible for the regulation of the immune response [38]. Th17 and Treg cells arise from the same naïve CD4+ T cells in different cytokine environments [39]. T cells are converted into Th17 cells by IL-1β, IL-6, IL-21 and transforming growth factor-β (TGF-β). Th17 cells produce IL-17 which, by affecting various cells, activates inflammation and induces RANKL, which activates osteoclasts [40]. Cytokines such as IFN-γ, IL-4 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which are created by Th1, Th2 and Treg cells, are responsible for the regulation of osteoclast differentiation. An imbalance between Th17 and Treg cells occurs in RA, and may play a role in the disease progression [31]. Th17 and Treg cells not only show opposite functional properties, but are also characterized by different cell markers: retinoic acid receptor-related orphan receptor variant 2 (RORC2) is a Th17 marker and forkhead box P3 (Foxp3) is a Treg marker [41]. Both Th17 and Treg cells control the proliferation of each other to maintain equilibrium. Pathogenic Th17 cells mediate pannus growth, osteoclastogenesis and synovial neoangiogenesis, while Treg cells function as a suppressor of autoreactive lymphocytes [42]. In recent years, several studies highlighted that miRNAs are important regulators of the immune response [43]. A few miRNAs, such as miR-155 and miR-146a, affect T cells function. As a result, they modulate autoimmune pathogenesis [44][45][46]. Moreover, the increase in miR-146a and miR-155 in peripheral blood mononuclear cells (PBMCs) from RA patients suggests that miRNAs can be involved at different levels in the regulation of RA pathogenesis [47].

3. microRNAs and Their Role in Rheumatoid Arthritis Pathogenesis

miRNAs are single-stranded, conserved, non-coding RNAs, 20–22 nucleotides in length. miRNAs have been the topic of many studies in recent times, and more than 2000 miRNAs have been identified to date. With every new study on miRNAs, it becomes more apparent that miRNAs take part in many biological functions, including cell proliferation and apoptosis. miRNAs direct gene expression post-transcriptionally, and control around one third of the genes in the human genome [48]. miRNAs are also responsible for regulating innate and acquired immunity by contributing to the generation of immune cells, including T cells, B cells and dendritic cells. “Changed” miRNAs initiate the creation of excessive autoantibodies and the secretion of inflammatory cytokines, leading to an immune system imbalance. In this way, miRNAs correlate with different autoimmune diseases, including RA [48][49]. A series of miRNAs were found to be uncontrolled in subsets of cells inside the articular compartment of RA patients, leading to the production of proinflammatory cytokines and the activation of leukocytes, which take part in the immunologic component of effector synovial pathology [50]. Numerous miRNAs related to inflammatory cytokines, synovial cell proliferation and osteoclast differentiation have been identified to date, and attempts have been made to use them in RA treatment [51][52]. Focusing on miRNAs will help to advance the treatment strategies for RA.
miRNAs are responsible for the determination of the expression of many genes. They have a critical part in supporting the improvement and function of the immune system, and many are active in the progress of autoimmune diseases. miRNAs such as let-7a, miR-26, miR-146a, miR-146b, miR-150 and miR-155 have been shown to be meaningfully upregulated in IL-17, producing cells leading to Th17 differentiation and promoting RA pathogenesis via IL-17 [53]. Furthermore, miR-146a, miR-155, miR-132 and miR-16 are responsible for the increase in PBMCs seen in patients with RA compared to healthy subjects [47].
The level of miRNA expression depends on the stage of RA development. In patients at an early stage of RA, serum levels of miR-16, miR-146a, miR-155 and miR-223 are lower than in patients with more advanced RA progression [54]. Furthermore, patients with RA in the earlier stage have a notably lower level of miR-16 and miR-223 in serum when compared to healthy controls, and these miRNAs may serve as biomarkers to better differentiate patients at an early stage of RA from healthy subjects [54].
As shown in Table 1, miR-16, miR-103a, miR-132, miR-145, miR-146a, miR-155, miR-221, miR-22 and miR-301a [8][47][55][56][57][58][59] were increased. These changes affect primarily cytokine secretion and disturbances in the balance between Th17 and Treg cells. For example, for miRNA146a, studies in vitro have shown how stimulation with IL-1 and TNF-α leads to the upregulation of miRNA146a in monocytic cell lines, and how this is regulated by nuclear factor kappa-beta (NF-κB). Other studies show that rheumatoid arthritis synovial fibroblast (RASF), when exposed to TNF-α, increased the expression of miRNA146a.
Table 1. List of increased levels of miRNA in PBMCs with their targeted genes [8].
Increased Level of miRNA Targets Subject of Studies
miR-16 Unknown Human
miR-103a AGO2, TP53 Human
miR-132 Unknown Human
miR-145 Unknown Human
miR-146a * IRAK1, TRAF6 Human
miR-155 * APAF1, CASP10, SHIP-1, SOCS1, Human and Murine
miR-221 Unknown Human
miR-222 Unknown Human
miR301a PIAS3 Human
Abbreviations: AGO: Protein argonaute-2, APAF1: Apoptotic protease activating factor 1, CASP10: Caspase 10, IRAK1: Interleukin-1 receptor-associated kinase 1, JNK: c-Jun N-terminal kinase, PIAS3: Protein inhibitor of activated STAT3, SHIP-1: Src homology 2-containing inositol phosphatase-1, SOCS1: Suppressor of cytokine signaling 1, TP53: Tumor protein p53, TRAF6: Tumor necrosis factor receptor-associated factor 6. * Are mentioned in more than one study.
 
Table 2 presents miR-21, miR-125b and miR-548a, which decreased in patients with RA [60][61][62]. Lin, S. et al. showed that miR-6089 is downregulated in RASF and synovial fibroblast-like synoviocytes. They observed that the overexpression of this miRNA restrained proliferation and promotes apoptosis and, on the other hand, lowers the secretion of inflammatory cytokines in RASF [63]. Many researchers show favorable correlations between TNF-α and PBMC miRNA146a expression in patients with RA [64]. By taking part in the downregulation of IL-1 and TNF-α production, this downregulation in PBMCs could lead to persistent proinflammatory cytokine production in patients with RA. miRNAs can act as a negative regulator for NF-κB, which leads to the downregulation of the protein levels of IRAK1 and TRAF6, which are the main particles downstream of TNF-α and IL-1 signaling [64].
Table 2. List of decreased levels of miRNA in PBMCs with their targeted genes [8].
Decreased Level of miRNA Targets Subject of Studies
let-7a ERK1, ERK2, K-Ras, JNK Human
miR-21 Foxp3, STAT3, STAT5 Human
miR-125b Unknown Human
miR-548 NF-κB pathway, TLR-4 Human
Abbreviations: ERK1/2: Extracellular signal-regulated kinase ½, Foxp3: Forkhead box P3, K-Ras: Kirsten rat sarcoma virus gene, NF-κB: Nuclear factor kappa-beta, TLR: Toll-like Receptor.

 

3.1. miRNAs Affecting Rheumatoid Arthritis Synovial Fibroblasts

As mentioned earlier, T cells have a crucial role in RA pathogenesis by activating synovial macrophages and RASFs [29]. Modifications in miRNA expression affect many features of RASFs’ tasks [65]. These changes influence intracellular pathways in RASFs by altering miRNA levels. It can be noticed in pathways such as NF-κB [66][67], JAK/STAT [68][69] and wingless/integrated (Wnt) [70], as well as Toll-like receptor 2 (TLRs) [71]. The disruption of miRNA levels impacts the secretion of proinflammatory cytokines and MMPs, and the proliferation and survival or extinction of RASF. Moreover, some authors have also shown that changes in miRNA levels may counteract inflammation, which leads to tissue damage. Changes in miRNA levels in RASFs and what are they targeting are presented in Table 3 and Table 4 [8].
Table 3. List of increased levels of miRNA in RASFs with their targeted genes [8].
Increased Level of miRNA Targets Subject of Studies
miR-18a TNFAIP-3 Human
miR-19 * TLR2 pathway Human
miR-21 NF-κB pathway Murine
miR-125b NF-κB pathway Human
miR-126 * PIK3R2 Human
miR-143 IGF1R, IGFBP5, Ras MAPK, p38 MAPK Human
miR-145 SEMA3A Human
miR-146a * IRAK-1, TRAF6 Human and Murine
miR-155 * IKBKE, JAK2, STAT3 Human and Murine
miR-203 * NF-κB pathway Human
Unknown change to miR-218 ROBO1, Wnt/β-catenin Human
miR-221 * Wnt, BMP Human and Murine
miR-222 Wnt/cadherin Murine
miR-223 * IL-17RD, NFI-A Human and Murine
miR-323 Wnt/cadherin Murine
miR-338 * NFAT5 Human
miR-346 Btk, TTP Human
miR-522 SOCS3 Human
miR-663 APC Human
Abbreviations: APC: Adenomatous polyposis coli gene, Btk: Bruton’s tyrosine kinase, IL-17RD: Interleukin 17 receptor D, IRAK: Interleukin-1 receptor-associated kinase, JAK: Janus kinase, NFAT5: Nuclear factor of activated T cells 5, NFI-A: Nuclear factor 1-A, NF-κB: Nuclear factor kappa-beta, PIK3R2: Phosphatidylinositol 3-kinase regulatory subunit 2, p38 MAPK: Mitogen-activated protein kinase, Ras MAPK:, ROBO1: Roundabout 1, SCDF1: Stromal cell-derived factor 1, Sirtuin1:, SEMA3A: Semaphorin-3a, SOCS3: Suppressor of cytokine signaling, STAT: Signal transducer and activator of transcription, TLR2: Toll-like receptor, TNFAIP-3: Tumor necrosis factor a-induced protein 3, TTP: Tristetraprolin, Wnt: Wingless/integrated, Wnt/β-catenin: Wingless/integrated/β-catenin, Wnt/cadherin: Wingless/integrated/cadherin. * Are mentioned in more than one study.
 
 
Table 4. List of decreased levels of miRNA in RASFs with their targeted genes [8].
Decreased Level of miRNA Targets Subject of Studies
miR-10b * BTRC, IRAK4, TAK1, TBX5 Human
miR-17 TRAF2 Human
miR-20a * ASK1, TXNIP Human and Murine
miR-22 Cyr61 Human
miR-23b IKK- α, TAB2, TAB3 Human and Murine
miR27a FSTL1, NF-κB pathway, TR4 pathway Human
miR-29a * STAT3 Human
miR-30-3p BAFF Human
miR-34 * XIAP Human
miR-124a * CDK2, MCP1 Human
miR-137 CXCL12 Murine
miR-140-5p SCDF1, Sirtuin1 Human
miR-152 * ADAM10, DNMT1 Human and Murine
miR-188-5p CEMIP Human
miR-192 Caveolin 1 Human
miR-199a RB1 Human
miR-204 ATF2 Human
miR-211 ATF2 Human
miR-212 SOX5 Human
miR-375 Wnt/FZD8 Murine
miR-539 OPN Human
miR-650 AKT2 Human
Abbreviations: ADAM10: A disintegrin and metalloproteinase domain-containing protein 10, AKT2: Protein kinase B 2, ASK1: Apoptosis signal-regulating kinase 1, ATF2: Activating transcription factor 2, BAFF: B cell-activating factor, Caveolin 1:, CDK2: Cyclin-dependent kinase 2, CEMIP: Cell migration-inducing and hyaluronan-binding protein, Cyr61: Cysteine-rich angiogenic inducer 61, CXCL12: C-X-C motif chemokine ligand 12, DNMT1: DNA (cytosine-5)-methyltransferase-1, FSTL1: Follistatin-like protein 1, IKK- α: IkB kinase a, MCP1: Monocyte chemoattractant protein 1, NF-κB: Nuclear factor kappa-beta, OPN:, SCDF1: Stromal cell-derived factor 1, Sirtuin1:, STAT: Signal transducer and activator of transcription, TAB: TAK1/MAP3K7 binding protein, TAK1: Transforming growth factor-beta-activated kinase 1, TBX5: T-box transcription factor 5, TRAF: Tumor necrosis factor receptor-associated factor, TR4 pathway:, Wnt: Wingless/integrated, Xiap: X-linked inhibitor of apoptosis protein. * Are mentioned in more than one study.

3.2. miRNA Affecting Signaling Pathways

The role of TNF-α in inflammatory arthritis is well known, and is a starting point for anti-TNF-α therapy. Various miRNAs have been stated to control positively, and others negatively, TNF-α signaling and expression in RA, mainly by targeting the components of the NF-κΒ pathway. miRNA 17-92 cluster in recent years was the topic of many studies, mainly in oncology and its involvement with tumorigenesis, but it was also studied for inflammation in recent times. miRNA 17-92 cluster consists of miR-17, miR-18a, miR-19a/b, miR-20 and miR92 [72]. Earlier studies have proven an anti-inflammatory function of miR-19 and miR-20 in RASFs by modifying TLR and MAPK, which are entailed with the TNF-α pathway. miR-17, by being under-expressed in synovial fibroblasts and the membranes of patients with RA, leads to an anti-inflammatory reaction by affecting MAPK, which is entailed with the TNF-α pathway [73]. miR-20 not only influences the MAPK signaling pathway, but it is also involved within the NLRP3-inflammasome pathway, whereby targeting TXNIP can lower NLRP3 expression [74]. RASF transfected with pre-miR-18 showed proinflammatory phenotypes through the activation of NF-κΒ pathways after stimulation with TNF-α (Figure 2) [75].
Figure 2. TNF (tumor necrosis factor) and TLR (Toll-like receptor) signaling pathways with the miRNAs that target them.
Other miRNAs are involved in TNF-α pathway. For example, it has been found that miR-451 overexpression may reduce RASF proliferation as well as reduce proinflammatory cytokines secretion by RASFs. [76]. RASFs with overexpressed miR-125b were found with proinflammatory phenotypes. Additionally, there were higher levels of TNF-α, IL-1β, IL-6 and phospho-p65, which have major roles in the NF-κΒ pathway [66]. Among the previously mentioned miRNAs, miR-146a has been shown to be a regulator of immune and inflammatory replies, as well as being highly expressed in synoviocytes, synovial tissues, PBMCs and the rest of the cells that expressed IL-17 in patients with RA [47][53][77][78][79]. A strong connection was reported between miR-146a and inflammation and the regulation of the proliferation of immune-regulated cells. This beneficial role for miR-146a in inflammatory and immune processes in RA could make it a possible novel target for RA therapy. Additionally, miR-146a has a crucial suppressing role for Treg cells, and the lack of miR-146a in Treg cells can lead to a breach of immunological tolerance [45].

3.3. Role of miRNAs in Inflammatory Responses

A few other miRNAs have been shown to be responsible for regulating immune and inflammatory responses in patients with RA; these are presented in Table 5. miR-19a/b was stated to have a negative role in the regulation of inflammation in the human model [80]. It was shown that miR-21 acts by preserving the balance between immune tolerance and activation [81]. The levels of miR-323-3p were discovered to be increased in RASF, and the gene encoding this miRNA can act as a biomarker of the immune and inflammatory response [82]. miR-155 has strong regulatory potential in various immune cells. A positive correlation between miR-155 and inflammation in patients with RA has been found [82], indicating that miR-155 takes part in immune reactions, which results in autoimmune arthritis. miR-155 might be the next novel target for RA therapy [49][83][84][85][86].
Table 5. Role of microRNAs (miRNAs) in immune and inflammatory responses in rheumatoid arthritis (RA) [8][87].
miRNAs Regulation of T Lymphocytes Inflammatory Response
Let-7a Positive regulator  
miR-16 Positive regulator  
miR-17   Negative regulator
miR-18   Positive regulator
miR-19a/b   Negative regulator
miR-20   Negative regulator
miR-21 Positive regulator  
miR-26 Positive regulator  
miR-125b   Positive regulator
miR-132 Positive regulator  
miR-146a Positive regulator Positive regulator
miR-146b Positive regulator  
miR-150 Positive regulator  
miR-155 Positive regulator Positive regulator
miR-203   Positive regulator
miR-223   Positive regulator
miR-323-3p Positive regulator Positive regulator
miR-451   Negative regulator

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