Nature Medicine
5, 623 - 628 (1999)
doi:10.1038/9467
VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis
during endochondral bone formationHans-Peter Gerber1, 4, Thiennu H. Vu2, 4, Anne M. Ryan3, Joe Kowalski1, Zena Werb2
& Napoleone Ferrara11
Departments of Cardiovascular Research, Genentech,
1 DNA Way, South San Francisco, California
94080, USA
3
Pathology, Genentech, 1 DNA Way, South San
Francisco, California 94080, USA
2
Department of Anatomy, Box 0452, University of California
Medical Center, San Francisco, California
94143, USA
4
H.-P.G and T.H.V. contributed equally.
Correspondence should be addressed to Napoleone Ferrara nf@gene.comHypertrophic 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.
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