Background/Purpose:

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) which reside in the hyperplastic lining layer of the synovium may 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.

Methods:

Synovial tissue biopsies were obtained from children with DA and JIA using ultrasound guided biopsies 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, where oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), reflecting oxidative phosphorylation and glycolysis respectively were quantified. Further metabolic outputs were assessed following the mitochondrial stress test where cells were treated with oligomycin, FCCP and antimycin A. Finally, glycolytic gene expression was assessed by Real-time PCR.

Results:

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. These effects were potentiated in response to TNFa stimulation. Metabolic activity was markedly different in DASFC vs JIASFC, with DASFC displaying increased basal metabolic activity compared to JIASFC. Moreover, following the mitochondrial stress test, a substantial increase in mitochondrial spare reserve capacity was observed in DASFC when compared to JIASFC, suggesting that DASFC have an enhanced ability to respond to sudden changes in the energy demands of the cell. Finally, an increase in metabolic genes HK2 and PDK2 were observed in DASFC vs JIASFC.

Conclusion:

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.

« Back to 2018 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/increased-invasive-capacity-and-metabolic-activity-in-synovial-fibroblasts-from-children-with-downs-arthropathy-compared-to-juvenile-idiopathic-arthritis/