Mice homozygous for null alleles ofFgfr3 exhibit skeletal overgrowth (Colvin et al 1996, Deng et al 1996) (Table 1). The contrasting phenotypes between the Fgfr3~j~ mice and the human dwarfing conditions resulting from mutations in Fgfrs suggest that the mutations causing dwarfism are gain-of-function alleles, a hypothesis strongly supported with biochemical data (Naski et al 1996, Webster et al 1996, Webster & Donoghue 1996). These gain-of-function and loss-of-function studies and the biochemical data define Fgfr3 as a negative regulator of endochondral bone growth.
Studies of Fgfr3 null mice show prolonged expression of markers for cell proliferation (Deng et al 1996) and over-expression of activated FGFR3 (achondroplasia mutation) in a chondrocytic cell line or in the growth plate of transgenic mice results in diminished cell proliferation (Naski et al 1998, Henderson et al 1999). In addition to affecting chondrocyte proliferation, FGFR3 may also regulate chondrocyte differentiation. Significantly, differentiation of cultured chondrocytes is inhibited by the addition of FGF2 (Kato & Iwamoto 1990). Histological studies of biopsies from individuals with achondroplasia show either extensive or focal disorganization of the growth plate (Ponseti 1970, Rimoin et al 1970, Briner et al 1991). Furthermore, Fgfr3~!~ mice have an expanded zone of hypertrophy in the epiphyseal growth plate (Colvin et al 1996, Deng et al 1996) and mice over-expressing activated FGFR3 in the growth plate show decreased numbers of cells in the prehypertrophic and hypertrophic zones (Naski et al 1998).
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