Meckel's and condylar cartilages anomalies in achondroplasia result in defective development and growth of the mandible.
Activating FGFR3 mutations in human result in achondroplasia (ACH), the most frequent form of dwarfism, where cartilages are severely disturbed causing long bones, cranial base and vertebrae defects. Because mandibular development and growth rely on cartilages that guide or directly participate to the ossification process, we investigated the impact of FGFR3 mutations on mandibular shape, size and position. By using CT scan imaging of ACH children and by analyzing Fgfr3Y367C/+mice, a model of ACH, we show that FGFR3 gain-of-function mutations lead to structural anomalies of primary (Meckel's) and secondary (condylar) cartilages of the mandible, resulting in mandibular hypoplasia and dysmorphogenesis. These defects are likely related to a defective chondrocyte proliferation and differentiation and pan-FGFR tyrosine kinase inhibitor NVP-BGJ398 corrects Meckel's and condylar cartilages defects ex vivo. Moreover, we show that low dose of NVP-BGJ398 improves in vivo condyle growth and corrects dysmorphologies in Fgfr3Y367C/+mice, suggesting that postnatal treatment with NVP-BGJ398 mice might offer a new therapeutic strategy to improve mandible anomalies in ACH and others FGFR3-related disorders.
INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France.|Service d'Odontologie, Hôpital Bretonneau, HUPNVS, AP-HP, Paris, France.
Martin
M
Biosse Duplan
INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France.
Davide
D
Komla-Ebri
UMR5199 PACEA, Université de Bordeaux, Bordeaux Archaeological Sciences Cluster Of Excellence, Université de Bordeaux, Bordeaux, France.
Yann
Y
Heuzé
INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France.
Valentin
V
Estibals
INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France.
Emilie
E
Gaudas
INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France.
Nabil
N
Kaci
INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France.
Catherine
C
Benoist-Lasselin
Neurochirurgie Pédiatrique, Unité de Chirurgie Craniofaciale, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
Michel
M
Zerah
Novartis Institutes for BioMedical Research, Basel, Switzerland.
Ina
I
Kramer
Novartis Institutes for BioMedical Research, Basel, Switzerland.
Michaela
M
Kneissel
Novartis Institutes for BioMedical Research, Basel, Switzerland.
Diana Grauss
DG
Porta
INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France.|Neurochirurgie Pédiatrique, Unité de Chirurgie Craniofaciale, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
Federico
F
Di Rocco
INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France laurence.legeai-mallet@inserm.fr.|Service de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
Laurence
L
Legeai-Mallet
D000130:Achondroplasia / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D000818:Animals; D002356:Cartilage / Q000002:abnormalities* / Q000254:growth & development / Q000503:physiopathology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D008334:Mandible / Q000002:abnormalities* / Q000254:growth & development / Q000503:physiopathology; D008335:Mandibular Condyle / Q000002:abnormalities* / Q000254:growth & development / Q000503:physiopathology; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D010671:Phenylurea Compounds / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*
D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C568950:infigratinib; D051498:Receptor, Fibroblast Growth Factor, Type 3