15A161

Down-Regulation of MiR-23a in Psoriatic Arthritis. Implications for Disease Pathogenesis

Author(s)

Sarah Wade, Michelle Trenkmann, Trudy McGarry, Douglas J Veale, Ursula Fearon.

Department(s)/Institutions

Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre University College Dublin, Ireland.

Introduction

Psoriatic Arthritis (PsA) is a chronic immunemediated inflammatory disease, characterised by proliferation of synovial tissue and progressive destruction of articular cartilage/bone, associated with psoriasis. These processes may be governed by microRNA (miRNA), a class of small noncoding RNAs which exert their function through suppression of specific target genes.

Aims/Background

Altered miR-23a expression has been previously associated with invasion, migration and proinflammatory mechanisms in other diseases. However, altered miRNA expression and it’s pathogenic implications have not been examined in PsA.

Method

Synovial tissue biopsies and peripheral blood mononuclear cells (PBMC) from PsA (n=8), osteoarthritis (OA) (n=7), and healthy controls (n=8). To examine possible factors involved in regulating miR-23a expression PsA synovial fibroblasts (SFC) were cultured with candidate proinflammatory stimuli including; TLR ligands (PAM, PolyIC, LPS), pro-inflammatory cytokines (TNF-α, IL-1β, IL-17). Total RNA was extracted using the Qiagen miRNeasy kit, and expression of miR-23a was measured by Sybr Green real-time PCR. In parallel, IL-6, IL-8 and MCP-1 were quantified in culture supernatants by ELISA. Clinical demographics such as CRP, TJC and SJC were also assessed.

Results

A significant increase in miR-23a expression was demonstrated in PsA PBMC versus OA (p=0.0476) and HC (p=0.0186). In contrast, a significant decrease in miR-23a expression was observed in PsA synovial tissue compared to OA (p=0.0172). MiR-23a synovial tissue expression inversely correlated with matched PBMC miR-23a expression (r=-1.00, p=0.0167) and DAS28-CRP (r= -0.5294, p=0.035). TLR activation via PolyIC (TLR3) and LPS (TLR4) significantly decreased miR-23a expression in PsA SFC (all p<0.05), with no effect observed for pro-inflammatory cytokines. This was paralleled by a significant induction of IL-6, IL-8 and MCP-1 in response to LPS and PolyIC (all p<0.05). Finally, in silico analysis identified PDE4B and PTK2B, genes involved in osteoclast function and multiple immune pathways, as potential targets for miR-23a.

Conclusions

We report altered expression and regulation of miRNA in PsA, levels of which were inversely associated with joint inflammation. MiR-23a may be an important regulator of pathogenesis in PsA and may represent a potential target for therapeutic strategies. Further work will examine the functional role of miR-23a and it’s implications on disease pathogenesis in PsA.