Antagonism of P2X7 receptor function in synovial fibroblasts is a potential therapeutic manipulation in rheumatoid arthritis.

In a recent article published in Science Advances, Rao et al. reported that synovial fibroblasts (SFs) from patients with rheumatoid arthritis (RA) express higher levels of P2X7 receptors (P2X7Rs) than SFs from patients with osteoarthritis [1]. EVT-401, a highly selective P2X7R antagonist with a marked preference for the human ortholog, inhibited the proliferation of RA SFs isolated from inflamed synovial tissue and maintained in culture for one day. EVT-401 also induced cell-cycle arrest in the G0/G1 phase. Incubation of RA SFs with TNFα increased P2X7R expression and was accompanied by enhanced IL-6 secretion, which was attenuated by EVT-401. RNA sequencing of TNFα-treated RA SFs revealed that EVT-401 downregulated the expression of genes involved in inflammatory responses. In humanized animal models of RA, EVT-401 demonstrated therapeutic efficacy, exerting direct anti-invasive and cartilage-protective effects on RA SFs. In conclusion, inhibition of P2X7R function in synovial fibroblasts may represent a promising therapeutic approach for patients with drug-refractory RA.