Rheumatoid arthritis is an autoimmune disease that cause non-septic proliferative synovitis and may compromise the integrity of bone and cartilage tissues, thus causing articular dysfunction [
16]. Epigenetics (chromatin rearrangement, histone modification and DNA methylation) have an important role in the occurrence and development of various autoimmune diseases [
17‐
21]. Genomic hypomethylation of T cells in RA patients can provoke the overexpression of some interleukins; in example, the interleukin-8 (IL-8) is overproduced by CD4+ T cells after the hypomethylation of its gene promoter [
22]. Moreover, the methylation of FOXP3 gene promoter region in CD4+ and CD25+ T cells is correlated to RA [
23]. Other DNA methylation sensitive genes were also identified (CD11a, CD70, CD10L/IgEFcRYI and perforin) [
24‐
27]. Yang et al. results showed elevated mRNA and protein expression levels of both CD11a and CD70 in RA patients derived CD4+ T cells tranfected with miR-126 plasmids, along with depressed DNMT1 protein but not mRNA levels. The introduction of a miR-126 inhibitor reversed such effects, suggesting the potential of elevated miR-126 expression in inducing the hypomethylation of CD11a and CD70 genes. Probably the depression of DNMT1 protein could cause the over-expression of CD11a and CD70, leading to the onset and progression of RA [
28]. Tumour necrosis factor alpha (TNFα), a key player in the development of RA, is known to induce macrophages and other immune system cells to produce pro-inflammatory mediators (IL-1, IL-6 and IL-8) [
29]; it also leads to T cell activation, and stimulate endothelial cells to express adhesion molecules [
29]. According Castro et al. the anti-TNFα therapy in RA patients upregulated their serum miR-126 profile; moreover, they found that miR-126 correlated to changes in the inflammatory parameters (CRP or ESR) [
30]. Another main pathophysiological aspect of RA is the high increase of resident synovial cells, also known as synovial fibroblasts (SFs, RASFs). During the inflammation process, SFs become hyperplastic, invasive, and highly migratory, reminiscent of tumour cells, and have a fundamental role in the pathogenesis of RA [
31‐
33]. Phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signalling pathway was reported in SFs; there, it showed an unusual activation state, which might lead to the imbalance of SFs proliferation and apoptosis. It was also shown that the gene coding for the PIK3R2 was targeted by microRNA-126 [
34,
35]. Gao et al. aimed to explore the associations between miR-126, PIK3R2 gene and PI3K/AKT signalling pathway in RASFs [
36]. In fact, direct targeting of SFs in RA was proposed as an objective for new therapies. Gao et al. showed that miR-126 targeting PIK3R2 could stimulate growth and apoptosis resistance of SFs by regulating PI3 K/AKT signalling pathway in RA [
36]. In addition, RASFs can also trigger the production of innate immunity products [
37]. Qu et al. aimed to deepen the influence of miR-126 on the cellular cycle of RASFs. As they reported, miR-126 regulated the PI3K-AKT signalling pathway, through improving proliferation and blocking apoptosis. A higher miR-126 expression could augment growth and proliferation of RASFs by inhibiting cell apoptosis and functions influencing the cycle from G0/G1 phase to S phase [
38]. High serum levels of miR-126-3p in RA patients were also confirmed by Murata et al. [
39]. Cysteine-rich 61 (CCN1) is an important pro-inflammatory cytokine in RA, so Cheng et al. studied its role in the angiogenesis, a detrimental event in the disease. According their results, CCN1 markedly repressed miR-126 expression in osteoblasts. Co-transfection of cells with miR-126 mimic abolished CCN1-induced VEGF production and angiogenesis [
40].