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. 1999 Jul 19;190(2):293-8.
doi: 10.1084/jem.190.2.293.

Vascular endothelial growth factor can substitute for macrophage colony-stimulating factor in the support of osteoclastic bone resorption

S Niida  1 , M Kaku, H Amano, H Yoshida, H Kataoka, S Nishikawa, K Tanne, N Maeda, S Nishikawa, H Kodama
Affiliations

Vascular endothelial growth factor can substitute for macrophage colony-stimulating factor in the support of osteoclastic bone resorption

S Niida et al. J Exp Med. .

Abstract

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.

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Figures

Figure 1
Figure 1
Immunohistochemical staining of femur sections for VEGFRs. Longitudinal sections of femurs of 3-wk-old +/? mice were stained with either anti–VEGFR-1 polyclonal antibody (A), AVAS12 anti–VEGFR-2 mAb (B), or rabbit IgG (C). Arrowheads indicate osteoclasts, and arrows indicate endothelial cells. Original magnifications: ×238.
Figure 4
Figure 4
Dependence of osteoclasts in the femurs of 2-mo-old op/op mice on endogenously produced VEGF. The mice were killed 3 d after the onset of the treatment. Longitudinal sections of femurs were stained for TRAP activity and counterstained with hematoxylin. Each micrograph represents a group of femurs from three animals. Arrows in B indicate mononuclear TRAP-positive cells. (A) No injection; (B) five consecutive injections of 100 μg anti-VEGF polyclonal antibody at 12-h intervals; (C) a single injection of 5 μg rhVEGF165. Original magnifications: ×103.
Figure 2
Figure 2
Resorption of bone trabeculae in the femurs of op/op mice by osteoclasts with the support of endogenous VEGF or exogenous rhM-CSF. The treatment was started at 12 d of age, and the mice were killed at 19 d of age. Longitudinal sections of femurs were stained by Mallory's azan. Each micrograph represents a group of femurs from three animals. (A) No injection; (B) a single injection of 5 μg rhM-CSF at 12 d of age; (C) a single injection of 5 μg rhM-CSF at 12 d of age, and six consecutive injections of 5 μg each of VEGFR-1/Fc chimeric protein and rhM-CSF at 12-h intervals during 16 and 18 d of age. Original magnifications: ×20.
Figure 3
Figure 3
Ability of VEGF to support in vitro generation of osteoclasts. Nonadherent bone marrow cells were cultured in the presence of rhVEGF165 alone (A), rhVEGF165 and rhRANKL (B and D), or rhM-CSF and rhRANKL (C and E) in the wells of 96-well plates (A–C) or on dentine slices (D and E) for 7 d. The cultures were either stained for TRAP activity (A–C) or examined by backscattered electron microscopy (D and E). Arrows in D indicate small resorption lacunae. Original magnifications (A–C): ×25. Bars (D and E): 50 μm.
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