Hypochondroplasia gain-of-function mutation in FGFR3 causes defective bone mineralization in mice
Léa Loisay, Davide Komla-Ebri, Anne Morice, Yann Heuzé, Camille Viaut, Amélie de La Seiglière, Nabil Kaci, Danny Chan, Audrey Lamouroux, Geneviève Baujat, J.H. Duncan Bassett, Graham R. Williams, Laurence Legeai-Mallet
Léa Loisay, Davide Komla-Ebri, Anne Morice, Yann Heuzé, Camille Viaut, Amélie de La Seiglière, Nabil Kaci, Danny Chan, Audrey Lamouroux, Geneviève Baujat, J.H. Duncan Bassett, Graham R. Williams, Laurence Legeai-Mallet
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Research Article Bone biology Genetics

Hypochondroplasia gain-of-function mutation in FGFR3 causes defective bone mineralization in mice

Abstract

Hypochondroplasia (HCH) is a mild dwarfism caused by missense mutations in fibroblast growth factor receptor 3 (FGFR3), with the majority of cases resulting from a heterozygous p.Asn540Lys gain-of-function mutation. Here, we report the generation and characterization of the first mouse model (Fgfr3Asn534Lys/+) of HCH to our knowledge. Fgfr3Asn534Lys/+ mice exhibited progressive dwarfism and impairment of the synchondroses of the cranial base, resulting in defective formation of the foramen magnum. The appendicular and axial skeletons were both severely affected and we demonstrated an important role of FGFR3 in regulation of cortical and trabecular bone structure. Trabecular bone mineral density (BMD) of long bones and vertebral bodies was decreased, but cortical BMD increased with age in both tibiae and femurs. These results demonstrate that bones in Fgfr3Asn534Lys/+ mice, due to FGFR3 activation, exhibit some characteristics of osteoporosis. The present findings emphasize the detrimental effect of gain-of-function mutations in the Fgfr3 gene on long bone modeling during both developmental and aging processes, with potential implications for the management of elderly patients with hypochondroplasia and osteoporosis.

Authors

Léa Loisay, Davide Komla-Ebri, Anne Morice, Yann Heuzé, Camille Viaut, Amélie de La Seiglière, Nabil Kaci, Danny Chan, Audrey Lamouroux, Geneviève Baujat, J.H. Duncan Bassett, Graham R. Williams, Laurence Legeai-Mallet

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Figure 1

The hypochondroplasia mutation induces a dwarf phenotype in both human and mouse model.

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The hypochondroplasia mutation induces a dwarf phenotype in both human a...
(A) X-rays of fetus (34 weeks of gestation) showing metaphyseal enlargement, trident acetabula, and squared ilia (red arrow) and a relative early cuboid ossification center appearance. (B–D) X-rays of HCH patients. (B) Three-year-old female showing slight tibial bending with elongation of the distal fibula. (C) Obliquity of the distal tibia metaphyseal growth plate of 5-year-old female. The leg bones are mildly short and the metaphyses are wide. (D) We noted an elongation of the distal fibula and broad internal ossified epiphyseal centers of the knee, squared iliac bones, and horizontal acetabular roofs in an 8-year-old male. Scale bar: 5 cm. (E–G) X-rays of patient hand extremities (E: 3-year-old female; F: 5-year-old male; G: 8-year-old male). We observed a bone carpal age delay (red arrows), a relative short and broad phalange (particularly the proximal and middle phalanges), and prominent ulnar styloid processes. Scale bar: 5 cm. (H) X-rays of both male and female Fgfr3Asn534Lys/+ mice and their control littermates from 7 days to 180 days of age showing a progressive skeletal phenotype in Fgfr3Asn534Lys/+ mice compared with Fgfr3+/+. Scale bar: 1 cm. (I) Alizarin red/Alcian blue staining of mouse femurs and tibiae on P1. Graphical representation of femur and tibia length. Scale bars: 1 mm. Fgfr3+/+ (n = 6) and Fgfr3Asn534Lys/+ (n = 7) P1 male and female mice. (J) Graphical representation of the body weight and naso-anal, femur, and tibia length of Fgfr3Asn534Lys/+ and Fgfr3+/+ male and female mice during development (P1, P7, P14, P21, P28, P42, P60, and P180). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by 2-tailed Student’s t test.