FGFR antagonists restore defective mandibular bone repair in a mouse model of osteochondrodysplasia
Abstract Gain-of-function mutations in fibroblast growth factor receptor (FGFR) genes lead to chondrodysplasia and craniosynostoses. FGFR signaling has a key role in the formation and repair of the craniofacial skeleton. Here, we analyzed the impact of Fgfr2- and Fgfr3-activating mutations on mandib...
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| Format: | Article |
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Nature Publishing Group
2025-01-01
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| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-024-00385-x |
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| author | Anne Morice Amélie de La Seiglière Alexia Kany Roman H. Khonsari Morad Bensidhoum Maria-Emilia Puig-Lombardi Laurence Legeai Mallet |
| author_facet | Anne Morice Amélie de La Seiglière Alexia Kany Roman H. Khonsari Morad Bensidhoum Maria-Emilia Puig-Lombardi Laurence Legeai Mallet |
| author_sort | Anne Morice |
| collection | DOAJ |
| description | Abstract Gain-of-function mutations in fibroblast growth factor receptor (FGFR) genes lead to chondrodysplasia and craniosynostoses. FGFR signaling has a key role in the formation and repair of the craniofacial skeleton. Here, we analyzed the impact of Fgfr2- and Fgfr3-activating mutations on mandibular bone formation and endochondral bone repair after non-stabilized mandibular fractures in mouse models of Crouzon syndrome (Crz) and hypochondroplasia (Hch). Bone mineralization of the calluses was abnormally high in Crz mice and abnormally low in Hch mice. The latter model presented pseudarthrosis and impaired chondrocyte differentiation. Spatial transcriptomic analyses of the Hch callus revealed abnormally low expression of Col11, Col1a, Dmp1 genes in mature chondrocytes. We found that the expression of genes involved in autophagy and apoptosis (Smad1, Comp, Birc2) was significantly perturbed and that the Dusp3, Dusp9, and Socs3 genes controlling the mitogen-activated protein kinase pathway were overexpressed. Lastly, we found that treatment with a tyrosine kinase inhibitor (BGJ398, infigratinib) or a C-type natriuretic peptide (BMN111, vosoritide) fully rescued the defective endochondral bone repair observed in Hch mice. Taken as a whole, our findings show that FGFR3 is a critical orchestrator of bone repair and provide a rationale for the development of potential treatments for patients with FGFR3-osteochondrodysplasia. |
| format | Article |
| id | doaj-art-11ccc852dca1438bbac008af6bfa342d |
| institution | Kabale University |
| issn | 2095-6231 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Bone Research |
| spelling | doaj-art-11ccc852dca1438bbac008af6bfa342d2025-01-26T12:19:47ZengNature Publishing GroupBone Research2095-62312025-01-0113111510.1038/s41413-024-00385-xFGFR antagonists restore defective mandibular bone repair in a mouse model of osteochondrodysplasiaAnne Morice0Amélie de La Seiglière1Alexia Kany2Roman H. Khonsari3Morad Bensidhoum4Maria-Emilia Puig-Lombardi5Laurence Legeai Mallet6Université de Paris Cité, Imagine Institute, Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR 1163Université de Paris Cité, Imagine Institute, Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR 1163Université de Paris Cité, Imagine Institute, Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR 1163Université de Paris Cité, Imagine Institute, Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR 1163B3OA UMR CNRS 7052, Université Paris CitéBioinformatics Core Platform, Imagine Institute, INSERM UMR1163 and Structure Fédérative de Recherche Necker, INSERM US24/CNRS UAR3633, Université Paris CitéUniversité de Paris Cité, Imagine Institute, Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR 1163Abstract Gain-of-function mutations in fibroblast growth factor receptor (FGFR) genes lead to chondrodysplasia and craniosynostoses. FGFR signaling has a key role in the formation and repair of the craniofacial skeleton. Here, we analyzed the impact of Fgfr2- and Fgfr3-activating mutations on mandibular bone formation and endochondral bone repair after non-stabilized mandibular fractures in mouse models of Crouzon syndrome (Crz) and hypochondroplasia (Hch). Bone mineralization of the calluses was abnormally high in Crz mice and abnormally low in Hch mice. The latter model presented pseudarthrosis and impaired chondrocyte differentiation. Spatial transcriptomic analyses of the Hch callus revealed abnormally low expression of Col11, Col1a, Dmp1 genes in mature chondrocytes. We found that the expression of genes involved in autophagy and apoptosis (Smad1, Comp, Birc2) was significantly perturbed and that the Dusp3, Dusp9, and Socs3 genes controlling the mitogen-activated protein kinase pathway were overexpressed. Lastly, we found that treatment with a tyrosine kinase inhibitor (BGJ398, infigratinib) or a C-type natriuretic peptide (BMN111, vosoritide) fully rescued the defective endochondral bone repair observed in Hch mice. Taken as a whole, our findings show that FGFR3 is a critical orchestrator of bone repair and provide a rationale for the development of potential treatments for patients with FGFR3-osteochondrodysplasia.https://doi.org/10.1038/s41413-024-00385-x |
| spellingShingle | Anne Morice Amélie de La Seiglière Alexia Kany Roman H. Khonsari Morad Bensidhoum Maria-Emilia Puig-Lombardi Laurence Legeai Mallet FGFR antagonists restore defective mandibular bone repair in a mouse model of osteochondrodysplasia Bone Research |
| title | FGFR antagonists restore defective mandibular bone repair in a mouse model of osteochondrodysplasia |
| title_full | FGFR antagonists restore defective mandibular bone repair in a mouse model of osteochondrodysplasia |
| title_fullStr | FGFR antagonists restore defective mandibular bone repair in a mouse model of osteochondrodysplasia |
| title_full_unstemmed | FGFR antagonists restore defective mandibular bone repair in a mouse model of osteochondrodysplasia |
| title_short | FGFR antagonists restore defective mandibular bone repair in a mouse model of osteochondrodysplasia |
| title_sort | fgfr antagonists restore defective mandibular bone repair in a mouse model of osteochondrodysplasia |
| url | https://doi.org/10.1038/s41413-024-00385-x |
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