Vascular Endothelial Growth Factor (VEGF) and Bone Morphogenetic Protein-4 (BMP-4) in Endochondral Ossification from Grafted Periosteum

Abstract

Vascular endothelial growth factor (VEGF) plays a very important role in vessel invasion during the process of endochondral ossification. Although grafted periosteum shows endochondral ossification, little is known about the role of VEGF in this process. Additionally, some reports have suggested that bone morphogenetic protein-4 (BMP-4) and VEGF work cooperatively in some way during endochondral ossification. In the present study we investigated, using immunohistochemical, histochemical, ultrastructural, and radiographic techniques, the role of VEGF and BMP-4 in bone formation from periosteal grafts taken from Japanese white rabbit tibia. By 14 days after grafting, fibroblasts in the grafted periosteum differentiated into chondrocytes to form cartilage. Some chondrocytes showed VEGF expression. Subsequent vessel invasion into cartilage from the VEGF immunopositive area coincided with commencement of endochondral ossification. Cartilage was replaced by newly formed bone by 35 days. Soft X-ray findings indicated calcification at 35 days after grafting. Chondrocytes and cartilage matrix were both BMP-4 positive. In newly formed bone, BMP-4 and VEGF expression was demonstrated in osteoblasts. These findings suggest that VEGF are related to vascular invasion into the grafted periosteum during endochondral ossification. Further, VEGF production in chondrocytes and osteoblasts may be related to BMP-4 production.