FGFR3 activating mutations are responsible for achondroplasia (ACH), the most common form of dwarfism. ACH clinical features include short stature, midface hypoplasia, frontal bossing and prognathism and both endochondral and membranous ossifications are disturbed. It is unknown if abnormal mandibles are present in ACH. To date, it is believed that primary (Meckels) and secondary (angular and condylar) cartilages play important roles in determining the final shape and position of the mandible. Here, we first characterized the mandibular anomalies in ACH patients and in Fgfr3Y367C/+ mice that mimic ACH. We analyzed CT scans of 16 patients and controls and observed that the condyle, formed by endochondral ossification, was shorter (−18%, P<0.05), broader (+11%, P<0.05) and projected forward. These condyle shape and position are associated with mandibular prognathism. Fgfr3Y367C/+ mice also exhibited a prognathic mandible. Morphometric analysis of uCT of the mandibles of Fgfr3Y367C/+ mice (n=7) and their control littermates (n=7) using anatomical landmarks and geometric morphometrics showed strong differences in shape and size. We observed in Fgfr3Y367C/+ mice that the body of the mandible was shorter from E16.5 (−12%, P<0.01) to P21 (−19%, P<0.005) and that the condyle, angle and mental protuberance were underdeveloped. We then explored Meckels cartilage and mandibular secondary cartilages of these mice and observed an abnormal proliferation and differentiation of the chondrocytes revealed with Ki67 and collagen type X immunolabeling. The replacement of Meckels cartilage by bone was delayed in these mice as showed with collagen I and TRAP labelling. Finally, we tested a FGFR3 tyrosine kinase inhibitor on ex vivo cultures of Fgfr3Y367C/+embryonic mandibles. After 6 days of culture, the cellular anomalies observed in Meckels cartilage were partially corrected. All together these data show that cartilages of the mandible are affected in ACH and that these defects contribute to the defective mandible shape and position.
17 May 2014 - 20 May 2014