Hypochondroplasia gain-of-function mutation in FGFR3 causes defective bone mineralization in mice
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 (Fgfr3A...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2023-06-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.168796 |
| _version_ | 1797634299541848064 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Léa Loisay |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:05:40Z |
| format | Article |
| id | doaj.art-70bb70a6bcf54661b19f721ef10cd021 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:05:40Z |
| publishDate | 2023-06-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-70bb70a6bcf54661b19f721ef10cd0212023-11-07T16:25:46ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-06-01812Hypochondroplasia gain-of-function mutation in FGFR3 causes defective bone mineralization in miceLéa LoisayDavide Komla-EbriAnne MoriceYann HeuzéCamille ViautAmélie de La SeiglièreNabil KaciDanny ChanAudrey LamourouxGeneviève BaujatJ.H. Duncan BassettGraham R. WilliamsLaurence Legeai-MalletHypochondroplasia (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.https://doi.org/10.1172/jci.insight.168796Bone biologyGenetics |
| spellingShingle | 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 Hypochondroplasia gain-of-function mutation in FGFR3 causes defective bone mineralization in mice JCI Insight Bone biology Genetics |
| title | Hypochondroplasia gain-of-function mutation in FGFR3 causes defective bone mineralization in mice |
| title_full | Hypochondroplasia gain-of-function mutation in FGFR3 causes defective bone mineralization in mice |
| title_fullStr | Hypochondroplasia gain-of-function mutation in FGFR3 causes defective bone mineralization in mice |
| title_full_unstemmed | Hypochondroplasia gain-of-function mutation in FGFR3 causes defective bone mineralization in mice |
| title_short | Hypochondroplasia gain-of-function mutation in FGFR3 causes defective bone mineralization in mice |
| title_sort | hypochondroplasia gain of function mutation in fgfr3 causes defective bone mineralization in mice |
| topic | Bone biology Genetics |
| url | https://doi.org/10.1172/jci.insight.168796 |
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