Increased Invasive Capacity and Metabolic Activity in Synovial Fibroblasts from Children with Downs Arthropathy Compared to Juvenile Idiopathic Arthritis
Sharon Ansboro, Charlene Foley, Monika Biniecka, Emma MacDermott, Douglas J. Veale, Ronan Mullan, Orla G Killeen and Ursula Fearon
Department of Molecular Rheumatology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin National Centre for Paediatric Rheumatology, Our Lady's Children's Hospital, Crumlin Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre, University College Dublin Tallaght Hospital
Downs Arthropathy (DA) is an inflammatory joint condition affecting children with Down syndrome, which is under-recognised, has a delayed diagnoses, resulting in chronic disability. Our clinical research showed an increased risk of arthritis in children with Down syndrome, with the prevalence in Ireland for DA 18-21 times greater than Juvenile idiopathic Arthritis (JIA). Furthermore children with DA had more erosive joint damage compared to JIA. This observed increase in erosive disease suggests that DA synovial fibroblasts (SFC) have a more invasive phenotype, however to date little is known about the underlying mechanisms that drive disease pathogenesis in DA.
The aim of the present study is to compare the function of primary synovial fibroblasts from children with DA vs JIA.
Synovial tissue biopsies were obtained from children with DA and JIA and assessed histologically for levels of vascularity, lining layer hyperplasia and sub-lining inflammation. Primary synovial fibroblasts were isolated from both DA and JIA and functional comparisons performed at passage 3. DASFC and JIASFC migration was assessed by wound repair scratch assays. Biocoat Matrigel™ Invasion Chambers were used to assess DASFC and JIASFC invasiveness. DASFC and JIASFC bioenergetic activity was assessed using the XFe96-Flux-analyser.
Synovial tissue analysis demonstrated a marked increase in synovial lining layer hyperplasia in DA vs JIA, with a median lining layer thickness score of 6(3-9) in DA vs 3(2-4) JIA, suggesting a more invasive pannus in DA compared to JIA. An increase in the migration of DASFC compared to JIASFC was observed, an effect paralled by a significant increase in the invasive capacity of DASFC vs JIASFC. Metabolic activity was markedly different in DASFC vs JIASFC, with DASFC displaying increased basal metabolic activity compared to JIASFC.
This is the first study to demonstrate differences in synovial pathology of children with DA vs JIA, demonstrating a marked increase in the invasive layer of DA synovium compared to JIA. This was paralleled by a significant increase in the migratory, invasive and bioenergetic profile of DASFC vs JIASFC, a phenotype that may contribute to the increased erosive disease observed in DA compared to JIA.