Hypoxia, Metabolism and Inflammatory Arthritis

Mitochondrial respiration is the main source of metabolic energy in cells by generating adenosine-triphosphate (ATP) in an oxygen-dependent manner.  Environmental cues such as the availability of nutrients and oxygen are sensed by mTOR, AMPK and HIF-1α together with inflammatory cell activation signals to determine the outcome of cell activation and differentiation. We have previously demonstrated that efficiency of oxygen supply to the synovium is poor due to the highly dysregulated synovial microvasculature. This along with the increased energy demands of activated infiltrating immune cells and inflamed resident cells leads to a hypoxic microenvironment and mitochondrial dysfunction. This favours an increase in reactive oxygen species, leading to oxidative damage which further promotes inflammation. In this adverse microenvironment synovial cells adapt and rapidly produce ATP to maintain cell activation/function and switch their cell metabolism from a resting regulatory state to a highly metabolically active state. This allows them to produce essential building blocks to support their proliferation. Therefore metabolic-reprogramming of synovial cells may provide novel therapeutic strategies for treatment of inflammatory arthritis.  However, the inflamed synovial tissue is composed of many different cell types including macrophages, T-and B-cells, dendritic cells, endothelial cells and synovial fibroblasts which through cell-cell interactions drive synovial invasiveness, thus understanding of these pathways is very complex. Therefore, our research programme aims to define the metabolic profile and signalling pathways in specific cells types isolated from the joint and in ex vivo organotypic synovial explant tissue from patients with IA. We have demonstrated distinct metabolic profiles and transcriptional signatures in specific cell types isolated from the joint. Furthermore, we have identified distinct subsets within specific cell types that differ in their metabolic profile, an effect that impacts on whether the cell is pro-inflammatory or pro-resolution.  Finally, we have identified that these changes occur very early in disease and can even be present pre-disease onset. Our ongoing work examines the therapeutic potential of targeting metabolic pathways using in-vitro, ex-vivo and in-vivo models.