Restrained chondrocyte proliferation and maturation with abnormal growth plate vascularization and ossification in human FGFR-3(G380R) transgenic mice

Hum Mol Genet. 2000 Jan 22;9(2):249-58. doi: 10.1093/hmg/9.2.249.

Abstract

Achondroplasia, the most common genetic form of human dwarfism, results from a point mutation (G380R) in the gene for fibroblast growth factor receptor 3 (FGFR-3). Heterozygotes for the mutation share disproportionate, proximal shortening of the limbs, mid-face hypoplasia and relative macrocephaly due to a failure in endochondral ossification. Here we have generated transgenic mice expressing the human mutant FGFR-3 under the transcriptional control of the mouse gene. Mice that are hemizygous for the mutant human gene display disproportionate dwarfism with skeletal phenotypes remarkably similar to those of human achondroplasia. Mice that are homozygous for the transgene suffer from a profound delay in skeletal development and die at birth, similar in that respect to humans homozygous for the achondroplasia mutant gene. Microscopic analysis of long bones demonstrates growth plate morphology compatible with that of human achondroplasia cases, sharing endochondral growth inhibition with restrained chondrocyte proliferation and maturation, penetration of ossification tufts and aberrant vascularization.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone and Bones / abnormalities*
  • Cell Differentiation / genetics
  • Cell Division / genetics
  • Chondrocytes / pathology*
  • Embryonic and Fetal Development / genetics
  • Fibroblast Growth Factors / genetics
  • Growth Plate / abnormalities*
  • Growth Plate / blood supply*
  • Growth Plate / chemistry
  • Humans
  • Mice
  • Mice, Transgenic / abnormalities*
  • Mice, Transgenic / genetics*
  • Osteogenesis / genetics
  • Protein-Tyrosine Kinases*
  • Receptor, Fibroblast Growth Factor, Type 3
  • Receptors, Fibroblast Growth Factor / genetics*

Substances

  • Receptors, Fibroblast Growth Factor
  • Fibroblast Growth Factors
  • FGFR3 protein, human
  • Fgfr3 protein, mouse
  • Protein-Tyrosine Kinases
  • Receptor, Fibroblast Growth Factor, Type 3