Impaired vitamin D signaling in VDRgem mutants reveals novel targets in tooth and alveolar bone

Teeth are established as targets for vitamin D metabolites but have retained less attention than the well-defined bone cell metabolism. Here we report that VDRgem mice, which bear a point-mutated vitamin D receptor unresponsive to the endogenous bioactive vitamin D, are more severely affected and have a greater severity of tooth and alveolar bone defects than VDR-null mice. Micro computed tomography (µCT) and histological analysis of adult VDRgem mice unravels severely reduced alveolar bone density, with abnormal root and pulp morphology. VDRgem mutants had severely hypocalcified alveolar bone and dentin- comparatively worse than VDR-null mice- as confirmed by scanning electron microscopy and mineral analysis. This genetically confirmed that vitamin D, acting through its receptor, enables bone and tooth to accumulate enough calcium and phosphorous for structural integrity. In addition, enamel structure was defective in VDRgem mice, displaying hypomineralized areas. Transcriptional profiling of postnatal day 5 VDRgem and VDR-null mutant incisors revealed vitamin D ligand signaling targets which promote mineralization, induce alveolar bone growth, assure dentin integrity, and regulate ribosomal protein synthesis. RNA sequencing analysis of VDRgem mutants uniquely showed defects in developmental targets- notably fibroblast growth factor and sonic hedgehog signaling reductions. Collectively, the severe defects in VDRgem tooth and alveolar bone demonstrate the importance of vitamin D actions during odontogenesis.