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Background This study aimed to determine the effects of total saponins from Rhizoma Dioscoreae Nipponicae (TS-RDN) on the expression of vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-2 and Tie-2 (endothelial tyrosine kinase receptor) receptors in the synovium of rats with rheumatoid arthritis (RA) (collagen-induced arthritis; CIA), and to examine the mechanisms of TS-RDN in alleviating RA. Methods The CIA rat model was established and the animals were randomly divided into control, CIA model, TS-RDN, diosgenin, and tripterygium groups. Fluorescent polymerase chain reaction was performed to detect VEGF expression in the rat knee joint synovium. Additionally, immunohistochemical assay was used to detect protein expression of Ang-2 and Tie-2 in the rat knee joint synovium. Results Expression of VEGF, Ang-2, and Tie-2 in the model group was significantly higher than in the control group ( p < 0.01). After TS-RDN, tripterygium and diosgenin treatment, VEGF and Ang-2 expression was lower than in the model group ( p < 0.01). However, Tie-2 expression showed no significant difference. The effects of TS-RDN on VEGF expression were more marked than those of tripterygium and diosgenin ( p < 0.01). Conclusion TS-RDN might reduce the expression of VEGF, Ang-2, and Tie-2 in the synovium, thus inhibiting synovial angiogenesis and playing a therapeutic role in RA. [ABSTRACT FROM AUTHOR]