Osteoclast-forming Activity of Vascular Endothelial Growth Factor

Colony-stimulating factor-1 (C SF-1) is an essential regulator of the differentiation, proliferation and survival of macrophage lineage cells including bone-resorbing osteoclasts. We have demonstrated that vascular endothelial growth factor (VEGF), a known angiogenic factor, can act as a substitute for CSF-1 function in osteoclastogenesis through the VEGF receptor-1. Osteopetrotic Csf1op/Csf1op (op/op) mice exhibit severe osteoclast deficiency owing to the lack of CSF-1 function. However, the deficiency is gradually reversed with aging, suggesting the existence of an alternative factor supporting osteoclastogenesis. We have found that the administration of VEGF to op/op mice induces a sufficient number of osteoclasts to ameliorate the osteopetrosis. Estrogen deficiency induces the acceleration of osteoclastic bone resorption mediated by the upregulation of bone-resorbing factors including CSF-1. Ovariectomized op/op mice exhibited upregulation of VEGF expression and an increase in number of osteoclasts. VEGF antagonists inhibited both spontaneous osteoclast recruitment in the aging op/op mice and estrogen deficiency-dependent increases in osteoclasts in OVX-op/op mice. These results clearly demonstrate an ability of osteoclastogenic activity of VEGF