Connective tissue growth factor (CTGF, a.k.a. CCN2) is inflammatory mediator and abundantly expressed in
osteoarthritis (OA). Angiogenesis is essential for OA progression. Here, we investigated the role of CTGF in
vascular endothelial growth factor (
VEGF) production and angiogenesis in OA synovial fibroblasts (OASFs). We showed that expression of CTGF and
VEGF in synovial fluid were higher in OA patients than in controls. Directly applying CTGF to OASFs increased
VEGF production then promoted endothelial progenitor cells tube formation and migration. CTGF induced
VEGF by raising miR-210 expression via PI3K, AKT, ERK, and nuclear factor-κB (NF-κB)/ELK1 pathways. CTGF-mediating miR-210 upregulation repressed
glycerol-3-phosphate dehydrogenase 1-like (GPD1L) expression and PHD activity and subsequently promoted
hypoxia-inducible factor (HIF)-1α-dependent
VEGF expression. Knockdown of CTGF decreased
VEGF expression and abolished OASF-conditional medium-mediated angiogenesis in vitro as well as angiogenesis in chick chorioallantoic membrane and
Matrigel-plug nude mice model in vivo. Taken together, our results suggest CTGF activates PI3K, AKT, ERK, and NF-κB/ELK1 pathway, leading to the upregulation of miR-210, contributing to inhibit GPD1L expression and
prolyl hydroxylases 2 activity, promoting HIF-1α-dependent
VEGF expression and angiogenesis in human synovial fibroblasts.