Developmental defects of enamel include amelogenesis imperfecta (AI) and molar-incisor hypomineralization (MIH). Both conditions affect the quality and quantity of enamel and severely disrupt oral functions in children with loss of occlusion, tooth sensitivity, and increased caries susceptibility. Children with AI or MIH have greater needs for dental treatment throughout their life and often exhibit dental behavioral management problems. While AI is a rare disease, MIH is found in many different populations with a prevalence from 2.4% to 40.2%. In both diseases the enamel organ epithelium is affected either by a gene mutation resulting in AI or by unknown factors resulting in MIH. The pathophysiology of AI and MIH is not understood and therapeutic options are limited to fluoride applications, restorations with poor retention and extractions. Enamel formation into the hardest mineral is promoted by enamel matrix proteins. As enamel accumulates mineral, the matrix converts from protein-rich to devoid of proteins. One of the enamel proteins is ameloblastin (Ambn) accounting for 5% of the enamel proteins. In hypomineralized enamel, the mineral content does not reach the necessary concentration. Ambn was identified in hypomineralized enamel of extracted teeth, but it is not clear if it plays a role in the pathogenesis of MIH. We have developed a mouse model to study the effect of Ambn concentration in AI and MIH-like enamel by under- or overexpressing ameloblastin in enamel organ epithelium. In mice with completely deleted Ambn the enamel is hypoplastic. When Ambn is overexpressed, as in patients with MIH, the enamel in these mice displays white, demarcated 'patches' that fracture easily from the dentin. The AI/MIH mouse model will serve to dissect the cellular and molecular events in enamel hypomineralization to identify strategies for the diagnosis, prevention and therapy of hypomineralized enamel. In the first aim, the hypothesis is tested that under- and over-expression of Ambn in mice is causally associated with AI-like and MIH-like disease phenotypes.
Specific Aim 2 will test the hypothesis that specific gene networks/pathways are differentially expressed in mice under- vs. over-expressing the Ambn gene including critical proximal regulators and downstream mediators. For this project clinicians and scientists were recruited with unique expertise in imaging techniques, proteomics and bioinformatics. Affected children will significantly benefit from discoveries derived from the proposed research. Advances in understanding the regulation of AI and MIH will lead to new strategies in diagnosis, prevention and treatment to improve the oral health of affected children.
Amelogenesis imperfecta and molar-incisor hypomineralization are developmental defects of the enamel affecting primary or permanent teeth with reduced mineral content apparent as discolored, sensitive teeth and breakdown of the enamel requiring extensive, advanced dental care life-long. Amelogenesis imperfecta is a rare disease; molar-incisor hypomineralization has a high prevalence in children between worldwide. We propose studies to investigate the pathophysiology in the cells of the enamel organ to find appropriate strategies for diagnosis, treatment and prevention of affected individuals.
| Pham, Cong-Dat; Smith, Charles E; Hu, Yuanyuan et al. (2017) Endocytosis and Enamel Formation. Front Physiol 8:529 |
