Dentin, the most abundant component of teeth, is a mineralized tissue produced by odontoblasts. Genetic disorders resulting in defective dentin mineralization are most commonly caused by mutations in genes coding for dentin matrix proteins or in phosphate metabolism genes, underscoring the critical role of matrix composition and phosphate homeostasis in proper dentin formation. However, the transcriptional control of odontoblast-regulated phosphate homeostasis and extracellular matrix mineralization is not well understood. Our preliminary data identified a novel transcription factor Trps1 as an important regulator of odontoblast function and dentin mineralization that targets primarily genes involved in phosphate homeostasis. Using in vivo and in vitro approaches, we uncovered that Trps1 deficiency in pre-odontoblasts is associated with downregulation of phosphatases initiating mineralization, and results in loss of the odontoblast mineralization potential. In turn, Trps1 upregulation in mature odontoblasts results in repression of dentin mineralization associated with downregulation of phosphate homeostasis genes that are involved in hypophosphatemic rickets. Based on these data we hypothesize that the role Trps1 plays in dentinogenesis is context-dependent: Trps1 supports initiation of dentin mineralization in newly differentiated odontoblasts, but in mature odontoblasts Trps1 acts as a repressor of mineralization. We propose mechanistic studies that will integrate Trps1 into molecular networks that control odontoblast differentiation and function, with specific focus on odontoblast-regulated phosphate homeostasis. Results of this project will define the molecular determinants of Trps1 context-dependent activity in odontoblasts and provide new insights into our understanding of the mechanisms underlying dentin mineralization disorders.

Public Health Relevance

Trps1 is a novel transcription factor that s involved in tooth development and tissue mineralization. Proposed studies address molecular and cellular mechanisms whereby Trps1 regulates the onset and progress of dentin mineralization. Results of this work will provide greater understanding of physiology and pathology of dentin.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE023083-01A1
Application #
8630687
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Wan, Jason
Project Start
2014-04-10
Project End
2019-03-31
Budget Start
2014-04-10
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$367,500
Indirect Cost
$117,500
Name
University of Alabama Birmingham
Department
Dentistry
Type
Schools of Dentistry
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Kuzynski, Maria; Goss, Morgan; Bottini, Massimo et al. (2014) Dual role of the Trps1 transcription factor in dentin mineralization. J Biol Chem 289:27481-93