VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation

Hypertrophic chondrocytes in the epiphyseal growth plate express the angiog enic protein vascular endothelial growth factor (VEGF). To determine the ro le of VECF in endochondral bone formation, we inactivated this factor throu gh the systemic administration of a soluble receptor chimeric protein (Flt- (1-3)-IgG) to 24-day-old mice. Blood vessel invasion was almost completely suppressed, concomitant with impaired trabecular bone formation and expansi on of hypertrophic chondrocyte zone. Recruitment and/or differentiation of chondroclasts, which express gelatinase B/matrix metalloproteinase-9, and r esorption of terminal chondrocytes decreased. Although proliferation, diffe rentiation and maturation of chondrocytes were apparently normal, resorptio n was inhibited. Cessation of the anti-VEGF treatment was followed by capil lary invasion, restoration of bone growth, resorption of the hypertrophic c artilage and normalization of the growth plate architecture. These findings indicate that VEGF-mediated capillary invasion is an essential signal that regulates growth plate morphogenesis and triggers cartilage remodeling. Th us, VECF is an essential coordinator of chandrocyte death, chondroclast fun ction, extracellular matrix remodeling, angiogenesis and bone formation in the growth plate.