The role of cellular metabolism in Rheumatoid and Psoriatic Arthritis
Clare Cunningham, PhD, Professor Douglas Veale, Professor Ursula Fearon
Centre for Arthritis and Rheumatic Diseases, St. Vincent’s University Hospital, Dublin, Ireland. University College Dublin, Trinity College Dublin
While Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PsA) share common features such as synovial hyperplasia, cartilage degradation and subchondral bone remodelling, their distinct differences, which aid their diagnosis, may account for the varying responses to specific treatments. Increased proliferation and angiogenesis transforms the synovium into an aggressive, tumour-like “pannus” which contributes to disease pathogenesis. Hypoxia, resulting from dysregulated angiogenesis, can cause cells to switch from mitochondrial respiration to anaerobic glycolysis in order to meet the cellular energy demand. The RA synovium is more hyperplastic and invasive than that of PsA, while a more abnormal vasculature is observed in the PsA synovium and correlates with a reduction in tissue pO2 levels.
The aim of this study was to compare the metabolic profiles of RA and PsA synovial fibroblast cells (SFC) and to determine whether there is a correlation between dysregulated metabolism, cell function and disease pathogenesis.
The metabolic profile of RA and PsA SFC was analysed using the XF96 Extracellular Flux Analyzer. Gene expression was determined by quantitative-PCR. SFC migration and invasion were observed by microscopy following wound-scratch and transwell invasion assays.
RA SFC displayed increased migratory capacity and invasiveness compared to PsA SFC. Expression of IL-6, IL-8 and the glycolytic markers, GLUT1/3, HK2, PKM1/2, PDK2 and LDHA is higher in RA SFC compared to PsA SFC. PsA SFC have a higher oxygen consumption rate (OCR), extracellular acidification rate (ECAR) and ECAR:OCR ratio than RA SFC.
Consistent with clinical observations, RA SFC have a greater migratory and invasive capacity than PsA SFC. Interestingly, despite the lower expression of glycolytic markers, PsA SFC display increased glycolysis compared to RA SFC and have a more glycolytic phenotype as indicated by a higher ECAR:OCR ratio. This may be due to the more hypoxic joint microenvironment. Further investigation is required to determine the precise role of metabolism in specific pathogenic processes.