The metabolic rewiring of tumor cells and immune cells has been viewed as a promising source of novel drug targets. Many of the molecular pathways implicated in rheumatoid arthritis (RA) directly modify synovium metabolism and transform the resident cells, such as the fibroblast-like synoviocytes (FLS), and the synovial tissue macrophages (STM), toward an overproduction of enzymes, which degrade cartilage and bone, and cytokines, which promote immune cell infiltration. Recent studies have shown metabolic changes in stromal and immune cells from RA patients. Metabolic disruption in the synovium provide the opportunity to use in vivo metabolism-based imaging techniques for patient stratification and to monitor treatment response. In addition, these metabolic changes may be therapeutically targetable. Thus, resetting metabolism of the synovial membrane offers additional opportunities for disease modulation and restoration of homeostasis in RA. In fact, rheumatologists already use the antimetabolite methotrexate, a chemotherapy agent, for the treatment of patients with inflammatory arthritis. Metabolic targets that do not compromise systemic homeostasis or corresponding metabolic functions in normal cells could increase the drug armamentarium in rheumatic diseases for combination therapy independent of systemic immunosuppression. This article summarizes what is known about metabolism in synovial tissue cells and highlights chemotherapies that target metabolism as potential future therapeutic strategies for RA.

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How macrophages are programmed to respond to monosodium urate crystals (MSUc) is incompletely understood partly due to the use of a toll-like receptor-induced priming step. Here, using genome wide transcriptomic analysis and biochemical assays we demonstrate that MSUc alone induces an in vitro metabolic and inflammatory transcriptional program in both human and murine macrophages markedly distinct from that induced by LPS. Genes uniquely up-regulated in response to MSUc belonged to lipids, glycolysis, and transport of small molecules via SLC transporters pathways. Sera from individuals and mice with acute gouty arthritis provided further evidence for this metabolic rewiring. This distinct macrophage activation may explain the initiating mechanisms in acute gout flares and is regulated through JUN binding to the promoter of target genes through activation of JNK (but not by P38) in a process that is independent of inflammasome activation. Finally, pharmacological JNK inhibition limited MSUc-induced inflammation in animal models of acute gouty inflammation.

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