OAT3 mediates methotrexate resistance in the treatment of rheumatoid arthritis

Objective: To study whether organic anion transporter 3 (OAT3) is involved in the development of methotrexate (MTX) resistance in the treatment of rheumatoid arthritis. Methods: The experimental components of the animals were the normal group, collagen-induced arthritis (CIA) model group, and MTX treatment group. MTX-treated rats were divided into the MTX effective group (MTX-E) and the MTX ineffective group (MTX-N). MTX-N receives additional treatment with OAT3 lentivirus injected into the joint cavity. Transient transfection was used to alter the expression of OAT3 in rat fibroblast-like synovial (rat-FLS). Results: The rate of effectiveness of MTX in treating CIA rats was 48.98%. Compared with CIA rats, MTX-E can greatly improve ankle joint synovial hyperplasia and joint damage, but MTX-N has no significant changes. The expression of OAT3 in the synovium of MTX-E was significantly higher than that of MTX-N. The MTX content in the MTX-E synovium was also higher than that in the MTX-N synovium. After injection of OAT3 overexpression lentivirus into the joint cavity of MTX-N, the effective rate of MTX reached 80%. The ankle synovial hyperplasia and joint damage were significantly improved in the overexpression group, and the MTX content was also significantly increased in the synovium. After rat FLS overexpressed OAT3, the inhibitory effect of MTX on rat FLS proliferation activity was significantly enhanced, and the absorption of MTX was also significantly increased, while silencing the expression of rat FLS OAT3 reversed the outcomes. Conclusion: OAT3 mediates the formation of MTX resistance and is a potential target for improving MTX resistance.