16A151

Decreased Expression of miR-125 in PsA Synovium Drives Joint Angiogenesis.

Author(s)

Sarah Wade, Nils Ohnesorge, Monika Biniecka, Trudy McGarry, Carl Orr, Breandán Kennedy, Douglas Veale, Ursula Fearon

Department(s)/Institutions

Centre for Arthritis and Rheumatic Diseases, St. Vincent’s University Hospital, Dublin, Ireland. University College Dublin Trinity College Dublin

Introduction

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 a key early pathogenic event in PsA which potentiates disease processes. 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-125, which has been previously associated with altered angiogenic, invasive and migratory processes. To date microRNA have been poorly investigated in PsA.

Aims/Background

To examine the expression and angiogenic associations of miR-125 in PsA.

Method

Synovial tissue biopsies, fibroblasts like synoviocytes (FLS), synovial fluid and PBMC were obtained from patients with PsA. MiR-125 levels were analysed by real-time PCR. Endothelial cells (HMVEC) were cultured in the presence of microRNA treated FLS supernatant to elucidate how microRNA regulates FLS angiogenic processes. Matrigel tube formation assays were performed to elucidate angiogenic functions. Synovial vasculature, determined by immunohistochemistry and RT-PCR, was compared mircoRNA expression. Clinical markers, including synovitis, vascularity, ESR, CRP, DAS28, ascertained at the time of arthroscopy, were correlated with synovial miRNA expression. The angiogenic function of miR-125 was confirmed In vivo using GFP tagged zebrafish.

Results

Expression of miR-125 was significantly decreased in PsA synovial biopsies compared to OA. MiR-125 levels were lower in SF mononuclear cells compared to peripheral blood, further supporting a decreased expression of miR-125 at the site of inflammation. Decreased expression of miR-125a in HMVEC displayed increased tube formations. Similarly, decreased expression of miR-125a in PsA FLS increased the ability of HMVEC to form tube networks. Synovial expression of miR-125 distinguished patients according to joint vascularity. Zebrafish treated with a morpholino designed to inhibit miR-125 displayed increased vascular sprouting just 5 days following treatment.

Conclusions

Our data demonstrates decreased expression of miR-125a in the joint of PsA patients and was strongly associated with joint vascularity and angiogenic mechanisms. This highlights the potential role of miR-125 in mediating key pro-angiogenic and thereby pro-inflammatory mechanisms in the synovium. Correcting these microRNA deficiencies, either by conventional pharmacological agents or as novel drug targets, or monitoring their expression may provide a therapeutic benefit especially in early disease stages.