MicroRNA-Mediated Epigenetic Regulation of Rheumatoid Arthritis Susceptibility and Pathogenesis

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.

Cuproptosis and cuproptosis–related genes in rheumatoid arthritis: Implication, prospects, and perspectives

“…The interaction between PDHB and NIMA-related kinase 10 ( NEK10 ) may be necessary for maintaining mitochondrial homeostasis, and NEK10 knockdown leads to increased mitochondrial damage and dysfunction ( 35 ). Thus, PDHB appears to be regulated by multiple miRNAs, while abnormalities in multiple miRNAs contribute to the pathological progression of RA, and the interconnection between the two deserves further exploration ( 36 ). In conclusion, downregulation of PDHB may contribute to the abnormal proliferative state of FLS in RA and may lead to defective Treg function through reduced binding to DJ-1.…”

Synovial Fluid Regulates the Gene Expression of a Pattern of microRNA via the NF-κB Pathway: An In Vitro Study on Human Osteoarthritic Chondrocytes

“…MiRNA are a class of small non-coding RNAs molecules, around 22 nucleotides long, which regulate gene expression by binding specific sequences within target messenger RNA (mRNA). A large number of evidence demonstrated that some miRNA are differentially expressed in OA cartilage samples and synovial tissue of OA and RA patients, confirming their role in the development and progression of these pathological conditions [ 25 , 26 , 27 ]. Some of the dysregulated miRNA target genes encoding for proteins implicated in extracellular matrix remodeling, pro-inflammatory activities, and redox balance in OA chondrocytes and RA fibroblast-like synoviocytes [ 27 , 28 , 29 ].…”

Absent in melanoma 2 (AIM2) in rheumatoid arthritis: novel molecular insights and implications

“…Thus, AIM2 plays an important role in suppressing T cells involved in autoimmunity by reducing AKT-mTOR signaling and altering immune metabolism, which enhances Treg cell stability [ 35 ]. In addition, noncoding ribonucleic acid (RNA)s are closely associated with RA [ 36 , 37 ], and a Treg/ T helper 17 (Th17) cell imbalance is a common pathological factor in RA [ 3 ]. Long-stranded noncoding RNA nuclear enriched abundant transcript 1 ( NEAT1 ) affects the balance between Treg/Th17 cells by inhibiting AIM2 through the microRNA(miR)-485-5p sponge.…”