Pathogenetic insights from the treatment of rheumatoid arthritis. Therefore, understanding the complex interplay between metabolic and inflammatory pathways in synovial cells in RA will provide insight into the underlying mechanisms of disease pathogenesis. Importantly, the inflamed synovium is a multicellular tissue, with cells differing in their metabolic requirements depending on complex cell–cell interactions, nutrient supply, metabolic intermediates and transcriptional regulation. Furthermore, it results in the accumulation of metabolic intermediates and alteration of redox-sensitive pathways, affecting signalling pathways that further potentiate the inflammatory response. This shift in metabolic capacity of synovial cells enables them to produce the essential building blocks to support their proliferation, activation and invasiveness. In inflamed joints, infiltrating immune cells and synovial resident cells have great requirements for energy and nutrients, and they adapt their metabolic profiles to generate sufficient energy to support their highly activated inflammatory states. In RA, the synovial microvasculature is highly dysregulated, resulting in inefficient oxygen perfusion to the synovium, which, along with the high metabolic demands of activated immune and stromal cells, leads to a profoundly hypoxic microenvironment. Activation of endothelium and immune cells is fundamental to the initiation of autoimmune diseases such as rheumatoid arthritis (RA), and it results in trans-endothelial cell migration and synovial fibroblast proliferation, leading to joint destruction.
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