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

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.

FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease

“…This relationship provides the first evidence for negative regulation of chondrogenesis by FGFR3. This genotypephenotype correlation is supported by several mouse models harboring activating mutations in FGFR3 (Table 1; Chen et al , 2001Li et al 1999;Wang et al 1999;Segev et al 2000;Iwata et al 2001).…”

Aspects of achondroplasia in the skulls of dwarf transgenic mice: A cephalometric study

“…However, the foramen magnum is not smaller in transgenic mice, but is actually relatively larger. Studies of various mouse models of achondroplasia discuss the anterior positioning of the foramen magnum but the question of its size or shape in mice has not been addressed, although figures in these papers clearly show the same lack of change in size or shape in the transgenic mice that we have observed (Table 4) (Deng et al, 1996;Wang et al, 1999;Segev et al, 2000). In humans, in contrast to mice, the narrow foramen magnum is due to abnormal endochondral growth of the cranial base as well as abnormal placement and premature fusion of the synchondroses (Hecht et al, 1989).…”

“…Skeletal and histological analyses showed that the mice had a shortened cranial base, hypoplasia of the midface, dome-shaped brain case with anteriorly displaced foramen magnum, and narrowed and distorted growth plates in long bones, vertebrae, and ribs. In a study by Segev et al (2000), a mouse model for human achondroplasia in which the mutated hFGFR3 cDNA (Gly380-to-Arg) was introduced into the mouse genome under the control of the mouse Fgfr3 promoter. Again, the phenotype is remarkably similar to human achondroplasia.…”

“…Fgfr3 null mice Naski 1998 Mutation targeted to growth plate cartilage in mice using regulatory elements from the collagen II gene Wang 1999 Introduced a G-to-A point mutation in the mouse Fgfr3 gene at codon 374 (the ortholog of human codon 380) Segev 2000 Mutated hFGFR3 cDNA (Gly380-to-Arg) was introduced into the mouse genome under the control of the mouse FGFR3 promoter Murakami, 2004 A constitutively active MEK1 cDNA was cloned into a vector containing a promoter/enhancer which directs the expression of the transgene to chondrocytes (Col2a1).…”

Dysplasies osseuses héréditaires et voies de signalisation associées aux récepteurs FGFR3 et PTHR1

“…Une mort prématurée par apoptose pourrait expliquer leur incapacité à s'hypertrophier efficacement. Ces conclusions tirées des travaux sur le cartilage et les chondrocytes de patients atteints de nanisme thanatophore sont confortées par les résultats de l'étude de modèles murins dans lesquels les mutations responsables de l'achondroplasie et du nanisme thanatophore ont été reproduites [25][26][27]. L'ensemble de ces résultats, ainsi que le phénotype des souris invalidées pour le gène Fgfr3, confirment le rôle de régulateur négatif de la croissance osseuse de FGFR3 [22].…”