Inhibitory effects of anti‐rheumatic drugs on vascular endothelial growth factor in cultured rheumatoid synovial cells

Vascular endothelial growth factor (VEGF) is a potent inducer of angiogenesis and is constitutively expressed in the synovium of rheumatoid arthritis (RA). Over‐expression of VEGF may play an important role in pathogenic vascularization and synovial hyperplasia of RA. In the present study, we examined whether disease‐modifying anti‐rheumatic drugs (DMARDs), including bucillamine (BUC), gold sodium thiomalate (GST), methotrexate (MTX) and salazosulfapiridine (SASP), act by inhibiting the production of VEGF by cultured synovial cells of patients with RA. Treatment of cultured synoviocytes with lipopolysaccharide (LPS) significantly increased VEGF production by cultured synovial cells. BUC significantly inhibited LPS‐induced VEGF production, while GST tended to inhibit the production of VEGF. The inhibitory effects on VEGF production were dose‐dependent. In contrast, MTX and SASP did not affect VEGF production. Reverse transcriptase‐polymerase chain reaction (RT‐PCR) analysis showed that BUC also inhibited LPS‐induced VEGF mRNA expression in RA synovial cells. The present study provides the first evidence that BUC inhibits VEGF production and the expression of its mRNA in synovial cells of RA patients. Our results indicate that the anti‐rheumatic effects of BUC are mediated by suppression of angiogenesis and synovial proliferation in the RA synovium through the inhibition of VEGF production by synovial cells.