Growth Plate Cartilage Studies in Achondroplasia

Horton, William A.; Hood, O. J.; Machado, Mirta A.; Campbell, Dianna

doi:10.1007/978-1-4684-8712-1_11

Cited by 12 publications

(7 citation statements)

References 3 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5). The growth plate shortening in the mutant mice was greater than that reported in most cases of human achondroplasia, although, in the human disease growth plate shortening also is observed to varying degrees (25,26). Comparison of the growth plates in dwarf and normal mice showed marked shortening with severe disorganization of the mutant growth plate in the long bones, as demonstrated in the growth plate of the tibia (Fig.…”

mentioning

confidence: 74%

A mouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3

Wang

Spatz

Kannan

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

212

158

View full text Add to dashboard Cite

Achondroplasia, the most common form of dwarfism in man, is a dominant genetic disorder caused by a point mutation (G380R) in the transmembrane region of fibroblast growth factor receptor 3 (FGFR3). We used gene targeting to introduce the human achondroplasia mutation into the murine FGFR3 gene. Heterozygotes for this point mutation that carried the neo cassette were normal whereas neo ؉ homozygotes had a phenotype similar to FGFR3-deficient mice, exhibiting bone overgrowth. This was because of interference with mRNA processing in the presence of the neo cassette. Removal of the neo selection marker by Cre͞loxP recombination yielded a dominant dwarf phenotype. These mice are distinguished by their small size, shortened craniofacial area, hypoplasia of the midface with protruding incisors, distorted brain case with anteriorly shifted foramen magnum, kyphosis, and narrowed and distorted growth plates in the long bones, vertebrae, and ribs. These experiments demonstrate that achondroplasia results from a gain-of-FGFR3-function leading to inhibition of chondrocyte proliferation. These achondroplastic dwarf mice represent a reliable and useful model for developing drugs for potential treatment of the human disease.Four fibroblast growth factor receptors (FGFRs) are known (1), and Ͼ50 mutations in three of them (FGFR1, 2, and 3) recently have been implicated in congenital skeletal and cranial disorders (reviewed in refs. 2-4). Achondroplasia, the most common form of dwarfism, was shown to be linked to a single point mutation, G380R, in the transmembrane region of FGFR3 (5, 6). FGFR3 is expressed mainly by developing bones, brain, lung, and spinal cord (7,8), and FGFR3-deficient mice show enhanced endochondral bone growth, expansion of their growth plate, and increased chondrocyte proliferation (9, 10). Thus, FGFR3 is a negative regulator of bone growth. Several experiments at the cellular level indicated that the Ach mutation (G380R) results in a constitutive activation of the receptor in a ligand-independent manner (11-13). It was suggested that this is because of stabilization of receptor dimers, a prerequisite for signal transduction in these receptors (14). This is also consistent with the constitutive activation by dimer formation described for an erbB2 (neu) receptor mutant, which carries a Val-to-Glu mutation in an analogous position to that of the FGFR3 variant in its transmembrane region (15). It is likely that, in many of the other mutations in FGFR1-3, the underlying mechanism of receptor activation is also through stabilization of receptor dimers because many of these mutations result in unpaired cysteines that may enhance inter-receptor disulfide bonds (2-4).To generate an animal model for this type of mutation and to study the role of the mutated FGFR3 in vivo, we used gene targeting to introduce the achondroplasia mutation (G380R) into murine FGFR3. This resulted in a dominant dwarf phenotype that exhibits many of the features of human achondroplasia. This is an indication from in vivo data for ...

show abstract

mentioning

confidence: 74%

A mouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3

Wang

Spatz

Kannan

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

212

158

View full text Add to dashboard Cite

show abstract

“…We previously reported peptide mapping results for achondrogenesis type 11, SED congenita and thanatophoric dysplasia [Horton et al, 1985[Horton et al, , 1987[Horton et al, , 1988a We have now extended the number of disorders screened to 20.…”

Section: Introductionmentioning

confidence: 95%

Type II collagen screening in the human chondrodysplasias

Horton¹,

Campbell

Machado

et al. 1989

Am. J. Med. Genet.

Self Cite

View full text Add to dashboard Cite

Abnormalities of type II collagen have been considered strong candidates for causing human condrodysplasias. We have employed peptide mapping to screen for several types of type II colagen abnormalities in cartilage samples from 66 patients with 20 separate disorders. Except for achondrogenesis type II (Langer-Saldino) and spondyloepiphyseal dysplasia (SED) congenita in which abnormalities have been described and diastrophic dysplasia in which the changes were probably secondary, no abnormalities were detected. Within the limitations of the screening technique, the results combined with other data from the literature suggest that abnormalities of this molecule are not common causes of chondrodysplasias outside of the achondrogenesis type II-SED congenita family of disorders.

show abstract

“…The condition is usually lethal in the neonatal period, but some patients have survived beyond early infancy [Pauli et al, 19831. Clinical, radiographic, and in some instances histopathological data of a few cases with homozygous achondroplasia have been reported [Hall et al, 1969;Rogovits et al, 1972;Rimoin et al, 1973;Yang et al, 1976;Kozlowski et al, 1977;Sillence et al, 1979;Horton et al, 1988;Aterman et al, 1983;Pauli et al, 1983;Mozkowitz et al, 19891. A more detailed study of the cartilage of homozygous cases might give hints concerning the pathogenetic mechanism of achondroplasia, We had the opportunity to perform histochemical, immunohistochemical, ultrastructural, and biochemical studies on the epiphyseal cartilage of a case of homozygous achondroplasia in which it was possible to obtain the tissue within a short period from death.…”

Section: Introductionmentioning

confidence: 95%

Homozygous achondroplasia: Morphologic and biochemical study of cartilage

Stănescu

Maroteaux

1990

Am. J. Med. Genet.

View full text Add to dashboard Cite

We have performed histochemical, immunohistochemical, electron microscopic, and biochemical studies on the upper tibial cartilage from a case of homozygous achondroplasia. The growth zone was narrow and disorganized. Columnization was absent except for a few areas with short rows of cells. Hypertrophy was reduced to scattered clusters of cells. The provisional calcification was patchy and primary trabeculae were thick and irregularly arranged. Islands of fibrous or fibrocartilagineous tissue were found along the growth zone. The matrix did not stain with safranin O and lacked metachromasia, except for pericellular rims around the hypertrophic cell clusters. Staining with antibodies against the large proteoglycan monomers and chondroitin-4-sulfate was weakly positive. Electron microscopic examination showed that only a few cells had degenerative signs. In most areas of the matrix, proteoglycan granules were absent. Areas with dense collagen fibers were seen. In contrast to the growth zone, the cartilage of the remaining epiphyses had normal histochemical, immunohistochemical, and electron microscopic appearance. The large proteoglycan monomers had a normal composition and hydrodynamic size. Type II and XI collagen, pepsin fragments of type IX collagen, and several noncollagenous proteins extracted from cartilage had a normal electrophoretic migration. It is suggested that a mutation affecting a matrix component or a regulatory pathway present only or predominantly in the growth area of the chondroepiphysis might explain the findings.

show abstract

Growth Plate Cartilage Studies in Achondroplasia

Cited by 12 publications

References 3 publications

A mouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3

A mouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3

Type II collagen screening in the human chondrodysplasias

Homozygous achondroplasia: Morphologic and biochemical study of cartilage

Contact Info

Product

Resources

About