Background Vascular endothelial growth factor (VEGF) has angiogenic, inflammatory and bony destructive roles on rheumatoid arthritis (RA).
Objectives This study was aimed to determine the unique role of VEGF on the osteoclastogenesis in RA.
Methods The expression of VEGF, receptor activator of nuclear factor kB ligand (RANKL) and CD55 in RA synovium was determined using confocal microscopy. VEGF and RANKL concentrations in synovial fluid and their correlation were determined using ELISA. VEGF-induced RANKL expression was determined in RA synovial fibroblasts using reverse transcription PCR, luciferase assays and ELISA. Peripheral blood monocytes were cultured with VEGF, and then osteoclastogenesis was assessed by counting tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells. Osteoclastogenesis was also determined in co-culture of monocytes with VEGF–pretreated synovial fibroblasts.
Results There was co-expression of VEGF, RANKL and CD55 in the lining and sublining area of RA synovium. RANKL concentration correlated with VEGF concentration in RA synovial fluid. VEGF stimulated the expression of RANKL mRNA and protein in RA synovial fibroblasts. RANKL promoter activity was upregulated by VEGF in the synovial fibroblasts transfected with RANKL reporter plasmids. The VEGF-induced RANKL expression was decreased by the inhibition of both VEGF receptor 1 and 2 pathways. VEGF induced osteoclast differentiation from monocytes in the absence of RANKL. When monocytes were co-cultured with VEGF-prestimulated RA synovial fibroblasts, monocytes were also differentiated into osteoclasts and the osteoclastogenesis decreased with inhibition of Src and PKC pathways.
Conclusions VEGF plays dual roles on osteoclastogenesis in RA: direct induction of osteoclastogenesis from the precursors and stimulation of RANKL production in synovial fibroblasts, which mediates by Src and PKC pathways. The axis of VEGF and RANKL could be a potential therapeutic target for RA-associated bone destruction.
Disclosure of Interest None declared