Rheumatoid Arthritis and Psoriatic Arthritis are chronic progressive autoimmune diseases affecting up to 2% of the population and are characterised by synovial proliferation and degradation of articular cartilage and bone. Targeted biologic therapies have improved the outcome, however a significant proportion of patients don’t respond, have sub-optimal responses, or experience adverse events. Therefore new treatment strategies are required to improve disease outcomes and potentially ‘a cure’. We previously demonstrated the architecture of the synovial-microvasculature is highly dysregulated resulting in a profoundly hypoxic microenvironment, inducing a cellular switch promoting synovial invasiveness and mitochondrial-dysfunction. This leads to a dramatic change in metabolic activity due to the increased cellular demand for energy, thus cells must adapt and rapidly produce ATP to maintain cell activation/function. Emerging evidence suggests that this metabolic shift induces a more activated inflammatory cell phenotype, where cells utilise glycolysis. Environmental cues such as the availability of nutrients and oxygen are sensed by mTOR, AMPK and HIF-1α and together with cell activation signals determine the phenotypic characterisation of inflammatory cells. Therefore we hypothesise that metabolicreprogramming of synovial cells may provide novel therapeutic strategies for treatment of RA and PsA. Specifically we will (i) compare the metabolic profile in tissues/cells from RA and PsA patients and correlate with disease activity and outcome, (ii) determine the effect of this metabolic shift on cell function/signalling using primary RA/PsA cell cultures and (iii) investigate the therapeutic potential of targeting metabolism on joint inflammation using an ex-vivo synovial-explant model, cartilage co-cultures and a human-mouse chimeric synovial/NSG mouse model.
