Defining the Role of Trps1 in Phosphate Mediated Mineralization

 描述(申请人提供)：矿化是磷酸钙(羟基磷灰石)晶体在细胞外基质中沉积的过程。磷酸盐的有效性是影响这一过程的关键因素之一。磷酸盐不仅作为羟基磷灰石晶体的一种成分来调节矿化，而且还作为一种信号分子诱导支持矿化的分子变化。已经证明，矿化细胞通过激活ERK1/2共同的信号转导蛋白和改变矿化相关基因的表达来响应磷酸盐。还发现这些基因的启动子富含GATA元件，表明它们受GATA转录因子的调控。大量研究表明，Trps1是一个GATA型转录因子，参与矿化基质的形成。首先，TRPS1基因的突变会导致三头犀牛指骨综合征(TRPS)或Ambras综合征，这两种综合征都表现出骨骼和牙齿的异常。此外，我们之前对Trps1缺乏或过度表达的小鼠的研究表明，Trps1在矿化过程中起到了作用。此外，我们的体外分析表明，成牙本质细胞中Trps1缺乏导致无法启动矿化；而Trps1上调导致矿化延迟和减少。全球基因表达分析表明，许多矿化相关基因的表达依赖于Trps1。在这些基因中，最不受调控的是那些与磷酸盐代谢有关的基因，这表明Trps1在磷酸盐信号/调节中发挥了作用。我们的初步数据进一步支持了这一点，该数据表明，在Trps1缺乏和Trps1过表达的细胞中，磷酸盐诱导的ERK1/2激活改变。尽管磷酸盐显然对矿化过程至关重要，但人们对这一过程的分子网络知之甚少。通过破译Trps1在磷酸盐介导的矿化中的作用，我们可以增加对矿化障碍发展的理解。

 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.