Figure 4. Metabolic intermediates in the RA joint.

The synovial pannus in the joints of patients with rheumatoid arthritis (RA) is a hypermetabolic lesion that demands high amounts of nutrients and oxygen to fulfil the energy and biosynthetic needs of its proliferative cells. The presence of glucose enables rapid and adaptive production of ATP, even under hypoxic conditions. Metabolic products such as lactate and ATP are released into the extracellular space, where they promote cell–cell communication and regulatory control. Lactate acidifies the tissue microenvironment and might directly contribute to cellular injury. With high levels of mitochondrial activity in tissue-resident and invasive cells, intermediates of the tricarboxylic acid cycle such as succinate and glutamate are secreted into the extracellular space. Signals transduced through specialized receptors (such as hydroxycarboxylic acid receptor 1 for lactate and succinate receptor 1 for succinate) regulate the functions of cells that sense extracellular metabolites. Here, metabolites serve as signalling molecules in cell–cell communication and in microenvironmental surveillance.