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Abstract
Endochondral ossification is a major mode of bone that occurs as chondrocytes undergo
proliferation, hypertrophy, cell death, and osteoblastic replacement. We have identified
a role for fibroblast growth factor receptor 3 (FGFR-3) in this process by disrupting
the murine Fgfr-3 gene to produce severe and progressive bone dysplasia with enhanced
and prolonged endochondral bone growth. This growth is accompanied by expansion of
proliferating and hypertrophic chondrocytes within the cartilaginous growth plate.
Thus, FGFR-3 appears to regulate endochondral ossification by an essentially negative
mechanism, limiting rather than promoting osteogenesis. In light of these mouse results,
certain human disorders, such as achondroplasia, can be interpreted as gain-of-function
mutations that activate the fundamentally negative growth control exerted by the FGFR-3
kinase.