To investigate the genetic and biochemical mechanisms used by FGFR3 to regulate chondrocyte growth and differentiation, we have constructed transgenic mice that either lack a functional Fgfr3 gene or that express the activating FGFR3 mutation (G380R) that causes achondroplasia. The effects on proliferation and differentiation of epiphyseal chondrocytes showed that activation of FGFR3 dramatically inhibits both chondrocyte proliferation and differentiation. The consequence of this effect on chondrogenesis is a histologically shortened growth plate and a gross phenotype resembling the human skeletal disorder, achondroplasia. In contrast, loss of FGFR3 activity results in an opposite phenotype in which proliferation is increased, the size and longevity of the growth plate is extended and skeletal overgrowth ensues. Examination of signalling pathways that regulate chondrocyte differentiation showed that FGFR3 signalling inhibits Ihh signalling and BMP4 expression in cartilage and perichondrium. These data place Fgfr3 genetically upstream of Ihh and suggest that FGFR3 and its endogenous ligand may globally regulate chondrogenesis and osteogenesis.
This work was supported by grants HD35692 and CA60673 from the National Institutes of Health, USA.
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