A Gain-Of-Function Mutation In FGFR2 Influences Mandibular Condylar Development On Mice

The skeleton is formed through intramembranous ossification and endochondral ossification. Mandibular condyle is formed through endochondral bone development. The development of the skeleton is regulated by numerous signaling molecules expressed in epiphyseal cartilage controlling both chondrogenesis and osteogenesis such as fibroblast growth factor receptor2 (FGFR2).A Ser252Trp mutation of FGFR2 can cause Apert syndrome (Apert syndrome, AS). Patients with heterozygous mutation in FGFR2 showed the severe craniofacial skeletal deformity and mandibular malocclusion, which indicated that the gain-of-function mutation in FGFR2 influenced mandibular condylar development. Previous studies have Confirmed that the Fgfr2+/S252W mice generated by using a Cre-mediated knock-in method, which mimicked human Apert syndrome, showed the severe craniofacial skeletal deformity and mandibular malocclusion as well. The Fgfr2+/S252W mice is a good animal model used to study the mandibular malocclusion.Objective:we introduced the gain-of-function Fgfr2+/S252W mice and explored the important effect of fibroblast growth factor receptor 2 (FGFR2) in the process of mandibular condylar growth, so as to provide theoretical basis for he etiology and treatment of temporomandibular joint disorder syndrome and mandibular malocclusion.Methods:1. We investigated mandibular condylar morphology by means of safranin-o/fast green staining at the stage of 1 week,3 weeks and 6 weeks.2. We assessed the expression of type X collagen (Col X) and vascular endothelial growth factor(VEGF) by immuncytochemistry staining and quantificational real-time PCR at the stage of 3 weeks.3. We detected osteoclastic activity in mandibular condyle by TRAP staining at the stage of 3 weeks.Results:1. The mutant mice appeared obvious mandibular malocclusion, while the wild-type littermates showed normal occlusion and the satisfactory intermaxillary relationship.2. The mutant mice displayed narrower width of the mandibular condylar growth plate, stronger stainings of trabecular bone at the stage of 1 week,3 weeks and 6 weeks and faster degradation of the calcified cartilage cell layer at the stage of 6 weeks.3. The expression of Col X and VEGF were increased in the mutant mice at the stage of 3 weeks (P<0.01)4. Osteoclastic activity was increased in the mutant mice at the stage of 3 weeks(P<0.001).Conclusion:The Fgfr2+/S252W mutant mice showed lower ability of proliferation and differentiation of condylar chondrocytes and stronger activity of the osteoclasts and hypertrophic chondrocytes than the wild-type littermates, which casued the cartilage matrix absorbed and trabecular bone ossified early. The gain-of-function mutation in FGFR2 resulted in histopathological abnormalities and development deformity of mandibular condyle cartilage in mice, causing mandibular malocclusion.