Abstract
Hypertrophic chondrocytes in the epiphyseal growth plate express the angiogenic protein vascular endothelial growth factor (VEGF). To determine the role of VEGF in endochondral bone formation, we inactivated this factor through 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 expansion of hypertrophic chondrocyte zone. Recruitment and/or differentiation of chondroclasts, which express gelatinase B/matrix metalloproteinase-9, and resorption of terminal chondrocytes decreased. Although proliferation, differentiation and maturation of chondrocytes were apparently normal, resorption was inhibited. Cessation of the anti-VEGF treatment was followed by capillary invasion, restoration of bone growth, resorption of the hypertrophic cartilage 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. Thus, VEGF is an essential coordinator of chondrocyte death, chondroclast function, extracellular matrix remodeling, angiogenesis and bone formation in the growth plate.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Bone and Bones / anatomy & histology
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Bone and Bones / physiology*
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Cartilage / anatomy & histology
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Cartilage / physiology*
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Cell Division
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Chondrocytes / cytology
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Chondrocytes / drug effects
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Chondrocytes / metabolism*
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Endothelial Growth Factors / physiology*
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Immunoglobulin G / genetics
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Immunoglobulin G / pharmacology
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Lymphokines / physiology*
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Mice
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Mice, Inbred C57BL
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Neovascularization, Physiologic / physiology*
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Osteogenesis / physiology*
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Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / pharmacology
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptor Protein-Tyrosine Kinases / pharmacology
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Receptors, Growth Factor / metabolism
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Receptors, Vascular Endothelial Growth Factor
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / pharmacology
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Recombinant Proteins / genetics
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Recombinant Proteins / pharmacology
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factor Receptor-1 / genetics
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Vascular Endothelial Growth Factor Receptor-1 / pharmacology
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Vascular Endothelial Growth Factors
Substances
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Endothelial Growth Factors
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Flt(1-3)-IgG
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Immunoglobulin G
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Lymphokines
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Platelet Endothelial Cell Adhesion Molecule-1
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Proto-Oncogene Proteins
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Receptors, Growth Factor
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Recombinant Fusion Proteins
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Recombinant Proteins
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Receptor Protein-Tyrosine Kinases
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Receptors, Vascular Endothelial Growth Factor
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Vascular Endothelial Growth Factor Receptor-1