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A8.13 TLR regulated MIR-23A down-regulated in psoriatic arthritis
  1. S Wade,
  2. M Trenkmann,
  3. T McGarry,
  4. C Orr,
  5. DJ Veale,
  6. U Fearon
  1. St. Vincent's University Hospital, Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre, Dublin 4, Ireland

Abstract

Background and purpose Psoriatic Arthritis (PsA) is amultifaceted disease associated with Psoriasis. Key pathogeneic mechanisms seen at all disease sites include angiogenesis, invasion, migration, proliferation and more specifically to joint involvement, osteoclastogenesis. These aberrant processes have been previously associated with dysregulated miRNA expression, a class of small non-coding RNAs which exert their function through suppression of specific target genes. More specifically, the miR-23a Cluster (miR-23a, miR-27a and miR-24–2) as in other chronic conditions, such as cancer.

Methods Synovial tissue biopsies and/or peripheral blood mononuclear cells (PBMC) were obtained from PsA (n = 8), osteoarthritis (OA) (n = 7), and healthy controls (n = 8). To determine factors involved in regulating miRNA expression, primary PsA synovial fibroblasts (SFC) were isolated and cultured with candidate pro-inflammatory stimuli including TLR ligands: Pam3CSK4 (1 µg/ml), LPS (1 µg/ml), polyIC (10 µg/ml) and pro-inflammatory cytokines: IL-1β (1 ng/ml), TNFα (10 ng/ml) and IL-17 (20ng/ml). MiR-23a, miR-27a and miR-24–2 expression was quantified by RT-PCR using RNU48 as an endogenous control. Clinical demographics such as synovitis, vascularity, DAS-28 CRP, TJC, SJC and patient global were also assessed.

Results All members of the miR-23a cluster, miR-23a, miR-27a and miR-24–2, were significantly decreased PsA synovial tissue versus OA (p = 0.0172). Synovial miR-23a expression negatively correlated with matched PBMC miR-23a (r=-1.00, p = 0.0167), demonstrating a dissociation in miR-23a expression between systemic and local inflammation. In addition, miR-23a expression in PsA synovial biopsies inversely correlated with DAS28-CRP (r= -0.5294, p = 0.035) and distinguished patient synovial vascularity and synovitis into high versus low groupings (all < 0.05). TLR activation via PolyIC (TLR3) and LPS (TLR4), but not Pam3CSK4 (TLR2), significantly decreased miR-23a expression in PsA SFC (all p < 0.05), with no effect observed for pro-inflammatory cytokines. Finally, in silico analysis identified putative targets for miR-23a, including PDE4B and PTK2B, which are known mediators in immune pathways, osteoclast function and angiogenic mechanisms.

Conclusion Our data provides evidence that the miR-23a cluster is significantly decreased in PsAsynovium. Synovial miR-23a levels, regulated by TLRs, correlate and distinguish clinical markers. Both previously confirmed and new potential targets identified here may have putative pathogenic implications for PsA pathogenesis. Thereby, the miR-23a cluster may represent a potential novel biomarker for disease activity or elucidate new therapeutic strategies.

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