Objectives: Osteopetrosis in osteopetrotic (op/op) mice exhibits an age-related correction in terms of increase in the number of osteoclasts irrespective of lack of functional macrophage colony-stimulating factor (M-CSF). Previous studies demonstrated that monocytes express fms-like tyrosine kinase (Flt-1), a receptor for vascular endothelial growth factor (VEGF), and VEGF stimulates monocyte chemotaxis. Meanwhile, it is well understood that orthodontic tooth movement is achieved by bone remodeling controlled by osteoclasts and osteoblasts. Moreover, angiogenesis is essential for orthodontic tooth movement to repair the tissue damage. Based upon these findings, the present study was designed to examine whether VEGF induces osteoclasts in op/op mice. Furthermore, we investigated the effects of VEGF injection on bone remodeling during experimental tooth movement. Methods: VEGF and placenta growth factor (PlGF), which is highly homologous to VEGF and combines only with Flt-1, were injected into op/op mice. Immunohistochemical staining of osteoclast for the detection of Flt-1 and fetal liver kinase (Flk-1) was examined. In normal mice, 0.5 ƒĘg VEGF was injected into the buccal gingival groove around the incisors subjected to mechanical stimuli°@from orthodontic appliance. Results: In VEGF and PlGF injection op/op mice, the number of osteoclasts was significantly larger than in the uninjected mice (p<0.01). Immunohistochemical staining suggested that osteoclast expressed Flt-1, but not Flk-1. In normal mice with an orthodontic appliance and VEGF injection, the number of osteoclasts appearing on the pressure side of the alveolar bone was increased markedly, and the rate of tooth movement was significantly enhanced (p<0.05). Conclusions: These results emphasize that VEGF is a critical factor for the differentiation of osteoclasts mediated with Flt-1, indicating a possibility of clinical application for modulating therapeutic bone remodeling essential for orthodontic and/or orthopedic treatment. This study was funded in part by a Grant-in-aid (No.14771179) from the Ministry of Education, Science, Sports and Culture in Japan.

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