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AB0156 Altered Expression and Regulation of Microrna in Psoriatic Arthritis
  1. S. Wade,
  2. M. Trenkmann,
  3. T. Mc Garry,
  4. D. Veale,
  5. U. Fearon
  1. Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre University College Dublin, Dublin, Ireland

Abstract

Background Psoriatic Arthritis (PsA) is a chronic immune-mediated inflammatory disease, characterised by proliferation of synovial tissue, progressive destruction of articular cartilage/bone, and is associated with psoriasis. It is now evident that these processes may be governed by microRNA (miRNA), a class of small non-coding RNAs which exert their function through suppression of specific target genes. Altered miR23a∼27a∼24-2 cluster expression has been previously associated with angiogenic, pro-inflammatory mechanisms and osteoblast differentiation. Abnormal miRNA expression has been previously demonstrated in rheumatoid arthritis, however to date their expression and regulation has not been examined in PsA.

Objectives To investigate if the miR-23a∼27a∼24-2 cluster contributes to PsA joint pathogenesis.

Methods Synovial tissue biopsies and peripheral blood mononuclear cells (PBMC) from PsA (n=8/8) and osteoarthritis (OA) (n=5/7) patients were collected. Expression levels of miR-30b, miR-21-5p and cluster partners, miR-23a and miR-27a, were quantified using the miRNA isolation kit (Qiagen) and Sybr Green real-time PCR. To investigate potential factors involved in the regulation of miRNA expression in the joint, primary PsA synovial fibroblasts (SFC) were cultured with pro-inflammatory stimuli including (TLR) ligands: Pam3CSK4 (1μg/ml), LPS (1μg/ml), Poly I:C (1μg/ml) and pro-inflammatory cytokines: IL-6 (20ng/ml), IL-17 (50ng/ml), IL-23 (20ng/ml), TNF-α (10ng/ml) and IL-1β (1ng/ml) and examined for miRNA expression.

Results A significant decrease in expression of miR-23a was demonstrated in PsA, compared to OA, synovial tissue (p<0.05). Similarly, both miR-30b and miR-27a showed decreased expression in PsA synovium versus OA (both p<0.065). In contrast, a significant increase in miR-23a expession was observed in PsA PBMC versus OA (p<0.05). This is consistent with studies suggesting dissociation between systemic and local inflammation. TLR ligands PolyIC (TLR3) and LPS (TLR4) significantly decreased miR-27a expression in PsA SFC (all p<0.05). In addition, PolyIC also significantly decreased miR-23a expression (p<0.05). Furthermore, synovial tissue miR-23a expression was inversely associated with the degree of macroscopic joint vascularity and radiographic severity in PsA. Finally, in silico analysis was utilised to identify putative miR-23a∼27a∼24-2 targets including TRIF, SOCS6 and NRP2.

Conclusions This is the first report to demonstrate altered expression and regulation of miRNA, at the site of inflammation, in PsA patients. PolyIC suppression of the miR-23a∼27a∼24-2 cluster may in turn impair their ability to suppress putative targets - TRIF, SOCS6 and NRP2, which are known to promote angiogenesis and persistent activation of inflammatory pathways. These data suggest a potential strategy for therapeutic targeting of miRNA in the treatment of PsA.

Disclosure of Interest S. Wade: None declared, M. Trenkmann: None declared, T. Mc Garry: None declared, D. Veale Grant/research support from: Abbvie,MSD,Pfizer,Roche, Consultant for: Pfizer,Roche, Speakers bureau: Abbott, MSD,Pfzier, Roche, U. Fearon: None declared

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