Defining the Role of Trps1 in Phosphate Mediated Mineralization



 DESCRIPTION (provided by applicant): Mineralization is the process in which crystals of calcium phosphate (hydroxyapatite) are laid down within the extra cellular matrix. The availability of phosphate is one of the critical factors affecting this process. Phosphate regulate mineralization not only as a component of hydroxyapatite crystals, but also as a signaling molecule that induces molecular changes supporting mineralization. It has been demonstrated that mineralizing cells respond to phosphate by activating the Erk1/2 common signal transduction proteins and by changing the expression of mineralization-related genes. It was also identified that promoters of these genes are enriched in GATA elements, suggesting that they are regulated by GATA transcription factors. Numerous studies suggest that Trps1, a GATA-type transcription factor, is involved in the formation of a mineralized matrix. First, mutations in the TRPS1 gene cause tricho-rhino-phalangeal syndrome (TRPS) or Ambras syndrome, both of which display skeletal and dental abnormalities. In addition, our previous studies using mice deficient for or overexpressing Trps1 have indicated a role for Trps1 in mineralization. Furthermore, our in vitro analyses show that Trps1-deficiency in odontoblastic cells results in an inability to initiate mineralization; whereas Trps1- upregulation results in delayed and decreased mineralization. Global gene expression analyses demonstrated that the expression of many mineralization-related genes depends on Trps1. Of these genes, the most dysregulated are those involved in phosphate metabolism, thus suggesting a role for Trps1 in phosphate signaling/regulation. This is further supported by our preliminary data demonstrating altered phosphate- induced Erk1/2 activation in Trps1 -deficient and Trps1-overexpressing cells. Although it is apparent that phosphate is critical for the mineralization process, little is known about the molecular network of this process. By deciphering the role of Trps1 in phosphate-mediated mineralization, we can increase our understanding of how mineralization disorders develop.