Postnatal Mandibular Growth in Alk2/Alk3 cKO Mice

Abstract

Ligands of the TGFβ superfamily (including BMPs, Activins, TGFβ, and GDFs) are known to play a crucial role in bone biology with multiple studies highlighting their importance in skeletal development, homeostasis, and fracture repair.1,4 Previous studies have shown that alterations in signaling through the type I BMP receptors, Alk2, Alk3, and Alk6 alone or in combinations, result in bone and cartilage defects, and influence bone development and growth.4 Pertinent to this thesis, it has been reported that Alk2 and Alk3 are critical for mandibular condylar development.8,23 However, few studies exist that examine the effects of BMP type I receptors on postnatal mandibular growth, where anomalies lead to malocclusions that affect oral health, general health, and quality of life. We removed Alk2 and Alk3 in Gli1+ progenitor cells including those in the mandible from P0-P5 using the inducible Gli1-CRE-ER (Alk2/3 cKO mice). No differences in mandibular length were detected at P10 in Alk2/3 cKO mice in comparison to Alk2/3fl/fl mice. At one month of age, Alk2/3 cKO mice displayed a smaller overall body size, shorter mandibular length and height, and reduced mandibular bone volume in comparison to controls. Additionally, the mandibular molar roots were shorter in the Alk2/3 cKO mice at one month. Our results indicate that BMP signaling through Alk2 and Alk3 is required for postnatal growth of the murine mandible in length, height, bone volume, and molar root length. Future studies are needed to evaluate if the smaller body size of the Alk2/3 cKO mice is due to changes in the ability of the mice to feed or due to effects of removing Alk2 and Alk3 in Gli1+ cells, which are present in many body tissues including the long bones, craniofacial bones, cervical loop of the incisors, periodontal ligament, adrenal cortex, gastrointestinal tract, and hair follicles. 11,18,19 It is possible that mandibular phenotypes observed in P28 Alk2/3 cKO mice are due to a combination of direct effects on BMP signaling in Gli1+ cells resident in the mandible and indirect effects of the mice being smaller overall.