Background Vascular endothelial growth factor (VEGF) is an angiogenic, inflammatory, and bony destructive molecule in the pathogenesis of rheumatoid arthritis (RA).
Objectives This study was aimed to determine the specific role of VEGF on the osteoclastogenesis in RA.
Methods The expression of VEGF, CD55, and receptor activator of nuclear factor kB ligand (RANKL) in RA synovial tissues was analyzed using confocal microscopy. VEGF-induced RANKL expression was determined in RA synovial fibroblasts using reverse transcription PCR, luciferase assays and ELISA. Osteoclastogenesis was assessed by counting tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells from the culture of isolated CD14+ monocytes with VEGF in the presence of signal inhibitors. Osteoclastogenesis was also determined after co-culture of monocytes with VEGF–pretreated synovial fibroblasts and CD4+ T cells.
Results There was co-expression of VEGF, RANKL and CD55 in lining and sublining area of RA synovium. The RANKL level correlated with the VEGF level in synovial fluid from RA patients. VEGF stimulated the expression of RANKL mRNA in RA synovial fibroblasts and RANKL promoter activity was upregulated by VEGF in the synovial fibroblasts transfected with RANKL reporter plasmids. VEGF-induced RANKL expression was decreased by the inhibition of Src and PKC. VEGF induced osteoclast differentiation from peripheral blood monocytes in the absence of RANKL. When monocytes were co-cultured with VEGF-prestimulated RA synovial fibroblasts, monocytes were differentiated into osteoclasts and the osteoclastogenesis decreased with inhibition of Src and PKC signaling.
Conclusions VEGF plays dual roles on osteoclastogenesis in RA: induction of osteoclastogenesis from the precursors and direct stimulation of RANKL production in synovial fibroblasts, mediated by Src and PKC pathways. The axis of VEGF and RANKL could be a potential therapeutic target for RA-associated bone destruction.
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Acknowledgements This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (NRF-2011-R1A4A007-0026961)
Disclosure of Interest None declared