Geniposide restricts angiogenesis in experimentary arthritis via inhibiting Dnmt1-mediated PTEN hypermethylation

Neovascularization in rheumatoid arthritis (RA) is a key bridge between malignant proliferative synovial tissue and pannus. In view of previous studies on the efficacy of Geniposide (GE) in experimentary arthritis, the purpose of this study was to investigate the possible mechanism of GE inhibiting angiogenesis by regulating the gene of phosphate and tension homology deleted on chromosome ten (PTEN). In this study, human umbilical vein endothelial cells (HUVEC) and Adjuvant arthritis (AA) rat models were performed to research in vitro and in vivo. The results showed that GE treatment significantly reduced synovitis and angiogenesis in AA rats, which may be associated with the increased expression of PTEN with GE treatment. Meanwhile, the hypermethylation of PTEN accompanied by the over-expression of DNA methyltransferases (Dnmts) was demonstrated in TNF-α-induced HUVEC and AA rats. Knockdown of DNMT1 by Dnmt1- siRNA significantly inhibited the tube formation of HUVEC in vitro. GE significantly restricted the angiogenesis of HUVEC by inhibiting DNA methylation, which was attributed to the down-regulation of DNMT1 rather than Dnmt3a and Dnmt3b. The anti-angiogenesis effect of GE was further verified in AA model by the inhibition of DNMT1. These results indicate that GE exhibited anti-angiogenesis effects in experimentary arthritis by inhibiting Dnmt1-mediated PTEN gene hypermethylation, which may brings new insights for the prevention and research of RA.