Skeletal dysplasia and defective chondrocyte differentiation by targeted overexpression of fibroblast growth factor 9 in transgenic mice

Mutations in fibroblast growth factor receptor 3 (FGFR3) cause several huma n chondrodysplasias, including achondroplasia, the most common form of dwar fism in humans, From in vitro studies, the skeletal defects observed in the se disorders have been attributed to constitutive activation of FGFR3. Here we show that FGF9 and FGFR3, a high-affinity receptor for this ligand, hav e similar developmental expression patterns, particularly in areas of activ e chondrogenesis. Targeted overexpression of FGF9 to cartilage of transgeni c mice disturbs postnatal skeletal development and linear bone growth. The growth plate of these mice exhibits reduced proliferation and terminal diff erentiation of chondrocytes similar to that observed in the human disorders . The observations provide evidence that targeted, in vivo activation of en dogenous FGFR3 inhibits bone growth and demonstrate that signals derived fr om FGF9-FGFR3 interactions can physiologically block endochondral ossificat ion to produce a phenotype characteristic of the achondroplasia group of hu man chondrodysplasias.