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 human chondrodysplasias, including achondroplasia, the most common form of dwarfism in humans. From in vitro studies, the skeletal defects observed in these disorders have been attributed to constitutive activation of FGFR3. Here we show that FGF9 and FGFR3, a high-affinity receptor for this ligand, have similar developmental expression patterns, particularly in areas of active chondrogenesis. Targeted overexpression of FGF9 to cartilage of transgenic mice disturbs postnatal skeletal development and linear bone growth. The growth plate of these mice exhibits reduced proliferation and terminal differentiation of chondrocytes similar to that observed in the human disorders. The observations provide evidence that targeted, in vivo activation of endogenous FGFR3 inhibits bone growth and demonstrate that signals derived from FGF9-FGFR3 interactions can physiologically block endochondral ossification to produce a phenotype characteristic of the achondroplasia group of human chondrodysplasias.
Garofalo
S
S
Research Department, Shriners Hospital for Children, Portland, Oregon, USA.
Kliger-Spatz
M
M
Cooke
J L
JL
Wolstin
O
O
Lunstrum
G P
GP
Moshkovitz
S M
SM
Horton
W A
WA
Yayon
A
A
D000818:Animals; D001846:Bone Development; D002454:Cell Differentiation; D002460:Cell Line; D019902:Chondrocytes / Q000378:metabolism*; D051525:Fibroblast Growth Factor 9; D005346:Fibroblast Growth Factors; D015870:Gene Expression; D006133:Growth Substances / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010009:Osteochondrodysplasias / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases; D051381:Rats; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics
C496460:Fgf9 protein, mouse; C496461:Fgf9 protein, rat; D051525:Fibroblast Growth Factor 9; D006133:Growth Substances; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; C496366:Fgfr3 protein, mouse; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3