Developmental defects of enamel include molar-incisor hypomineralization (MIH). This condition affects the quality and quantity of enamel and severely disrupts oral functions in children with loss of occlusion, tooth sensitivity and increased caries susceptibility. Children with MIH have greater needs for dental treatment throughout their life and often exhibit dental behavioral management problems. MIH is found in many different populations worldwide with a prevalence ranging from 2.4% to 40.2%. The enamel organ epithelium is affected by unknown factors resulting in MIH. The pathophysiology of MIH is not understood. Therapeutic options are limited to conventional therapy with fluoride applications, restorations often with poor retention and extractions. Enamel formation into the hardest mineral is promoted by enamel matrix 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 overexpression in MIH-like enamel in enamel organ epithelium. When Ambn is overexpressed, the enamel in these mice displays white, demarcated ?patches? that fracture easily from the dentin. The 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. We have developed transgenic mice with demarcated, MIH-like lesions in enamel. Our preliminary results show that the lesions enlarge as the ameloblastin (Ambn) concentration increases. Normally, enamel matrix is rapidly processed, degraded and internalized by ameloblasts, but when Ambn is overexpressed, the enamel matrix lingers on and the accumulation of mineral is hampered, manifesting as hypomineralized enamel. We have developed tools to accurately quantify mineral content and enamel volume with microCT methods. In a transcriptome analysis of enamel organ epithelium pathways for enamel matrix, enzymatic degradation, protein trafficking and ion handling were dysregulated. Our overall hypothesis is that overexpressed ameloblastin influences the mechanisms of enamel formation resulting in MIH lesions in enamel. In SA1 we will determine the onset of demarcated opacities within the phased formation of enamel in mice overexpressing Ambn. In SA2, we will determine the biological pathways of endocytosis of enamel proteins in vivo and in vitro as a consequence of ameloblastin overexpression. In SA3, we will determine if endocytosis of overexpressed Ambn can be promoted in Ambn mice by increasing the enzymatic activity in the enamel matrix. For the proposed studies a team of clinician scientists, experts in quantitative imaging, proteomics and bioinformatics has been assembled for unique interaction and novel approaches.

Public Health Relevance

Molar-incisor hypomineralization is a developmental defect of the dental enamel affecting primary and permanent teeth with reduced mineral content apparent as discolored, sensitive teeth and brittle enamel requiring advanced dental care life-long. Molar-incisor hypomineralization has a high prevalence in children worldwide. We propose studies to investigate the events in the cells of the enamel organ involved in the formation of enamel to find defined therapeutic avenues for affected individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
3R01DE026769-02S1
Application #
9763684
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Wan, Jason
Project Start
2018-12-01
Project End
2022-03-31
Budget Start
2018-12-01
Budget End
2019-03-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Texas Health Science Center
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Pham, Cong-Dat; Smith, Charles E; Hu, Yuanyuan et al. (2017) Endocytosis and Enamel Formation. Front Physiol 8:529