Altered expression of microRNA-23a in psoriatic arthritis modulates synovial fibroblast pro-inflammatory mechanisms via phosphodiesterase 4B
2019
Abstract Objectives To investigate the functional role of
miR-23a in synovial fibroblasts (SFC) activation in
psoriatic arthritis(PsA). Methods Differential expression of the
miR-23a-27a-24-2 cluster was identified by real-time quantitative PCR in PsA synovial tissue and peripheral blood mononuclear cells (PBMC) compared to osteoarthritis (OA) and correlated with disease activity. For regulation experiments, PsA synovial fibroblasts (SFC) were cultured with Toll-like receptor (TLR) ligands and pro-inflammatory cytokines. PsA SFC were transfected with a
miR-23a inhibitor to assess the functional effect on migration, invasion and expression of pro-inflammatory meditators. The direct interaction between
miR-23a and predicted target mRNA, phosphodiesterase 4B (
PDE4B), was examined by luciferase reporter gene assay, with the expression and regulation confirmed by RT-PCR and western blot. A PDE4 inhibitor was used to analyse the function of
PDE4Bsignalling in both
miR-23a and Poly(I:C)-induced PsA SFC activation. Results Synovial tissue expression of
miR-23a was lower in PsA compared to OA and correlated inversely with disease activity and
synovitis. TLR activation via Poly(I:C) and LPS, but not Pam3CSK4, significantly decreased
miR-23a expression, with no significant effect observed in reponse to stimulation with pro-inflammatory cytokines. Decreased
miR-23a expression enhanced PsA SFC migration, invasion and secretion of IL-6, IL-8, MCP-1, RANTES and VEGF. We identified
PDE4Bas a direct target of
miR-23a and demonstrated enhanced mRNA and protein expression of
PDE4Bin anti-
miR-23a transfected PsA SFC. Poly(I:C) and/or
miR-23a-induced migration and enhanced cytokine expression was suppressed by the blockade of PDE4 signalling. Conclusions In PsA, dysregulated
miR-23a expression contributes to synovial inflammation through enhanced SFC activation, via
PDE4Bsignalling, and identifies a novel anti-inflammatory mechanism of PDE4 blockade.
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