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02.25 Mir125 mediates angiogenic mechanisms in psoriatic arthritis
  1. Sarah Wade1,
  2. Nils Ohnesorge2,
  3. Stephaine Merrigan2,
  4. Monika Biniecka1,
  5. Trudy McGarry1,
  6. Brendan Kennedy2,
  7. Douglas Veale3,
  8. Ursula Fearon1
  1. 1Molecular Rheumatology, school of medicine, Trinity College Dublin, Ireland
  2. 2UCD School of Biomolecular and Biomedical Sciences UCD, Conway Institute University College Dublin, Belfield, Dublin, Ireland
  3. 3St Vincent’s University Hospital, Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre, Dublin, Ireland

Abstract

Introduction Psoriatic arthritis (PsA) is characterised by an early vascular phase which is essential in perpetuating pannus growth, immune responses and disease progression. Whilst established therapies, including methotrexate, anti-TNFs and Vitamin3D analogues, have demonstrated anti-angiogenic properties a greater molecular understanding is required to further harness these beneficial effects. Herein we propose microRNA, miR-125, has a fundamental role in orchestrating joint angiogenesis as characterised by ex-vivo associations, in-vitro assays and novel in-vivo zebrafish models.

Aims To elucidate the molecular role of miR-125 in regulating synovial angiogenesis and in response to therapy in PsA.

Methods MiRNA levels were quantified in synovial tissue (ST), synovial fluid (SF) and PBMC by RT-PCR and compared to clinical markers. Immunohistochemical analysis of vascular markers, VEGF, ANG2 and factor VIII were compared with microRNA expression. Matrigel tube formation and migration assays were performed to elucidate the angiogenic functions of miR-125 in endothelial cells (HMVEC) and fibroblast like synoviocytes (FLS). HMVECs were cultured in hypoxic tPO2 levels similar to joint conditions. GFP-tagged zebrafish embryos treated with anti-125 morpholinos, or vitaminD3 analogue, calcitrol, were monitored for angiogenic development.

Results MiR-125 was significantly decreased in PsA ST compared to OA. Similarly, miR-125 expression was lower SFMCs compared to PBMC, suggesting that miR-125 is decreased at the site of inflammation. Synovial expression of miR-125 was inversely associated with both increased macroscopic and microscopic vascularity, and in HMVEC miR-125 expression decreased in response to hypoxia. Decreased expression of miR-125a in HMVEC and FLS displayed increased tube formation and/or migrational mechanisms. Zebrafish with decreased miR-125 displayed increased vascular sprouts. In contrast, Calcitriol significantly reduced vascular development and increased the expression of miR-125, promoting miR-125 as a potential mechanism for orchestrating angiogenic development in vivo and in response to pharmaceutical agents.

Conclusion Our data demonstrates decreased expression of miR-125 in PsA and in-vivo models was strongly associated with pro-angiogenic mechanisms. Correcting these deficiencies, either by conventional pharmacological or as novel drug targets, may provide therapeutic benefit, especially in early disease.

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