Background/Purpose: MicroRNAs (miRNA) belong to a class of small, evolutionarily conserved, noncoding RNAs that function as post-transcriptional repressors of gene expression. An accumulating body of evidence suggests that up to 50% of the human genome is regulated by miRNAs.  The aim of this study was to examine expression, regulation and function of miRNA-125a-5p in inflammatory arthritis (IA).

Methods:  Synovial tissue biopsies and primary synovial fibroblasts (SFC) were obtained from patients with Psoriatic arthritis (PsA), Rheumatoid Arthritis (RA) and osteoarthritis (OA). MiR125a-5p levels were analyzed by real-time PCR and data was calculated by the deltaCt method using RNU6B as an endogenous control. To examine possible factors involved in regulating miR125a-5p expression, primary synovial fibroblasts (SFC) and microvascular endothelial cells (HMVEC) were cultured with candidate pro-inflammatory stimuli including; TLR ligands (PAM, PolyIC, LPS), pro-inflammatory cytokines (TNFa, IL-1b, IL-17) and growth factors (VEGF, Ang2). Overexpression/silencing of miR-125a-5p was analysed using a synthetic precursor of Pre or Anti-miR™-125, respectively. Cell invasion, tube formation and migration were examined using transwell invasion, angiogenic and wound repair assays, and pro-inflammatory mediators were quantified by ELISA.

Results: Expression of miR125a-5p was significantly higher in PsA and RA synovial biopsies and/or synovial fibroblasts compared to OA (p<0.05; p<0.05), with highest expresson observed in PsA (p<0.05). Angiogenic growth factor Ang2 induced miR125a-5p in synovial fibroblasts and HMVEC (p<0.05), with no effect observed for TLR ligands or pro-inflammatory cytokines. Silencing of miR by transfection with anti-miR-125a-5p resulted in inhibition of cell invasion, angiogenic tube formation and IL-6 expression. This is consistent with in silico analysis where prediction algorithms identified members of the IL-6 signalling pathway (IL-6R, gp130) as potential targets of miR-125a-5p. 

Conclusion:  Our data provides evidence that miR125a-5p is significantly increased in the inflammed joint, particularly in PsA.  High miR125a-5p expression in PsA and regulation by key angiogenic factor Ang2, is consistent with a possible role for miR125a-5p in the regulation of angiogenic mechanisms. MiR125a-5p also mediated cell migration, angiogenesis and IL-6 expression, key processes involved in the pathogenesis of PsA and RA. In conclusion, miR-125a-5p may be an important regulator of pathogenic mechanisms in inflammatory arthritis and may represent a potential novel target for future therapeutic strategies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mir125a-5p-mediates-angiogenic-mechanisms-in-inflammatory-arthritis/