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A8.12 Decreased expression of MIR-125A in psoriatic arthritis. Implications for joint pathogenesis
  1. S Wade,
  2. M Connolly,
  3. C Orr,
  4. DJ Veale,
  5. U Fearon
  1. St. Vincent's University Hospital, Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre, Dublin 4, Ireland

Abstract

Background and aims Psoriatic Arthritis (PsA) is a chronic immune-mediated inflammatory disease, characterised by proliferation of synovial tissue and destruction of articular cartilage/bone with associated psoriasis. Dysregulated angiogenesis is one of the key early pathogenic processes in PsA. These processes may be governed by microRNA (miRNA), a class of evolutionary conserved short non-coding RNAs which function as post-transcriptional repressors of gene expression. On such miRNA is miR-125a-5p which, in cancer, has been previously associated with altered angiogenesis, invasion and migration.

Objectives To examine the expression and angiogenic associations of miR-125a-5p in PsA.

Methods Synovial tissue biopsies and peripheral blood mononuclear cells were obtained from patients with PsA, osteoarthritis (OA) and/or healthy controls (HC). MiR-125a-5p levels were analysed by real-time PCR using RNU48 as an endogenous control. To examine possible factors involved in regulating miR125a-5p expression, primary synovial fibroblasts (SFC) and microvascular endothelial cells (HMVEC) 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). Immunoistochemical analysis was performed using factor VIII (DAKO) and appropriate IgG controls, on cryostat synovial tissue sections. Clinical markers, including synovitis, vascularity, ESR, CRP, DAS28, ascertained at the time of arthroscopy were correlated with synovial miRNA expression.

Results Expression of miR-125a-5p was significantly decreased in PsA synovial biopsies (n = 8) compared to OA (n = 4) (p < 0.05). No significant difference was observed at the PBMC level across PsA (n = 6), RA (n = 5) and Healthy controls (n = 5). Angiogenic growth factor, Ang2, induced miR-125a-5p in HMVEC (p < 0.05). Lower synovial expression of miR-125a-5p displayed a higher degree of factor VIII staining compared to patients with higher miR-125a-5p expression. This was further demonstrated in representative arthroscopic images.

Conclusion Decreased expression of miR-125a-5p in the joint and it’s association with vascularity, which is a hallmark of PsA, suggests it may be important in mediating key pro-angiogenic/pro-inflammatory mechanisms in the synovium. Correcting these microRNA deficiencies, either by conventional pharmacological agents or as novel targets, may provide a therapeutic benefit, especially in early disease stages.

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