Transcriptional Regulation of Dentin Mineralization

项目总结/文摘

PROJECT SUMMARY/ABSTRACT 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.