Vascular Endothelial Growth Factor Can Substitute for Macrophage Colony-stimulating Factor in the Support of Osteoclastic Bone Resorption

Correspondence to: Shumpei Niida, Department of Anatomy, Hiroshima University School of Dentistry, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan., sniida{at}ipc.hiroshima-u.ac.jp (E-mail), 81-82-257-5621 (phone), 81-82-257-5621 (fax)

We demonstrated previously that a single injection of recombinant human macrophage colony-stimulating factor (rhM-CSF) is sufficient for osteoclast recruitment and survival in osteopetrotic (op/op) mice with a deficiency in osteoclasts resulting from a mutation in M-CSF gene. In this study, we show that a single injection of recombinant human vascular endothelial growth factor (rhVEGF) can similarly induce osteoclast recruitment in op/op mice. Osteoclasts predominantly expressed VEGF receptor 1 (VEGFR-1), and activity of recombinant human placenta growth factor 1 on osteoclast recruitment was comparable to that of rhVEGF, showing that the VEGF signal is mediated through VEGFR-1. The rhM-CSF–induced osteoclasts died after injections of VEGFR-1/Fc chimeric protein, and its effect was abrogated by concomitant injections of rhM-CSF. Osteoclasts supported by rhM-CSF or endogenous VEGF showed no significant difference in the bone-resorbing activity. op/op mice undergo an age-related resolution of osteopetrosis accompanied by an increase in osteoclast number. Most of the osteoclasts disappeared after injections of anti-VEGF antibody, demonstrating that endogenously produced VEGF is responsible for the appearance of osteoclasts in the mutant mice. In addition, rhVEGF replaced rhM-CSF in the support of in vitro osteoclast differentiation. These results demonstrate that M-CSF and VEGF have overlapping functions in the support of osteoclastic bone resorption.

Key Words: osteoclasts, vascular endothelial growth factor, vascular endothelial growth factor receptor, macrophage colony-stimulating factor, osteopetrosis

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