The effect of vascular endothelial growth factor on osteoclastogenesis in rheumatoid arthritis

• Published in: PloS one Vol. 10; no. 4; p. e0124909
• Main Authors: Kim, Hae-Rim, Kim, Kyoung-Woon, Kim, Bo-Mi, Cho, Mi-La, Lee, Sang-Heon
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20-04-2015; Public Library of Science (PLoS)
• Subjects: Acid phosphatase; Acid phosphatase (tartrate-resistant); Acid resistance; Angiogenesis; Arthritis; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; Biocompatibility; Cell Differentiation - drug effects; Enzyme-linked immunosorbent assay; Female; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - pathology; Gene Expression Regulation - drug effects; Humans; Inflammation; Inhibition; Intracellular Space - drug effects; Intracellular Space - metabolism; Luciferase; Male; MAP kinase; Middle Aged; Monocytes; Monocytes - drug effects; Monocytes - pathology; Osteoclastogenesis; Osteoclasts; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteoclasts - pathology; Osteoprogenitor cells; Pathways; Peripheral blood; Plasmids; Protein kinase C; RANK Ligand - genetics; Receptors; Rheumatoid arthritis; Rheumatoid factor; Signal Transduction - drug effects; Src protein; Synovial fluid; Synovial Fluid - drug effects; Synovial Fluid - metabolism; TRANCE protein; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - pharmacology; Vascular endothelial growth factor receptors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0124909

Vascular endothelial growth factor (VEGF) has angiogenic, inflammatory, and bone-destructive roles in rheumatoid arthritis (RA). We aimed to determine the unique role of VEGF in osteoclastogenesis in RA. VEGF-induced receptor activator of nuclear factor ҡB ligand (RANKL) expression was determined in RA synovial fibroblasts by real-time PCR, luciferase assays, and ELISA. Osteoclastogenesis in peripheral blood monocytes cultured with VEGF was assessed by determining the numbers of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells. Synovial fluid RANKL was correlated with VEGF concentration in the RA patients. VEGF stimulated the expression of RANKL in RA synovial fibroblasts. The 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 receptors (VEGFR) 1 and 2, Src, protein kinase C (PKC) and p38 MAPK. VEGF induced osteoclast differentiation from monocytes in the absence of RANKL and this was decreased by the inhibition of VEGFR1 and 2, Src, PKC and p38 MAPK. On coculturing with VEGF-prestimulated RA synovial fibroblasts, the monocytes differentiated into osteoclasts, and the osteoclastogenesis decreased by inhibition of Src and PKC pathways. VEGF plays dual roles on osteoclastogenesis in RA: direct induction of osteoclastogenesis from the precursors and stimulation of RANKL production in synovial fibroblasts, which is mediated by Src and PKC pathways. The axis of VEGF and RANKL could be a potential therapeutic target for RA-associated bone destruction.