It has been reported that vascular endothelial growth factor (VEGF) 165 and placenta growth factor (PlGF) can induce differentiation of osteoclasts via Flt-1, because Flt-1 is the common receptor of these two factors. However, little is known about osteoclast differentia-tion via Flk-1, which is one of the main receptors for VEGF165. VEGF-E showed potent stimulatory activity to endothelial cell growth vascular permeability similar to those of VEGF165 via Flk-1 but not Flt-1. The purpose of this study was to clarify whether VEGF-E can induce osteoclast and the receptors of VEGF families for osteoclast differentiation. Ten μg VEGF-E was injected into 11-day-old op/op mice and the number of osteoclasts was ob-served 3 days after the injection. The effects of both Flt-1- and Flk-1- neutralizing antibodies against the injection of VEGF165 were also observed. Finally, the expression of these recep-tors in osteoclast precursors (OCP) was examined. After VEGF-E injection into op/op mice, many osteoclasts were induced. However, the number was less than that induced by VEGF165. The number of osteoclasts induced by VEGF165 was significantly reduced by the injection of either Flt-1- or Flk-1- neutralizing antibodies. Flt-1 and Flk-1 were clearly de-tected in OCP at both the mRNA and protein levels. We concluded that VEGF-E can also induce many osteoclasts in op/op mice. Furthermore, it is suggested that the VEGF165 signal for osteoclast differentiation is mediated via both Flt-1 and Flk-1.