All ETDs from UAB

Advisory Committee Chair

Dobrawa Napierala

Advisory Committee Members

Amjad Javed

Michael Miller

Selvarangan Ponnazhagan

Rosa Serra

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Mineralization is a tightly controlled bi-phasic process that occurs when crystals of calcium and phosphate (Pi) are laid down within the extracellular matrix. However, the molecular networks regulating the initiation and progression of this process have not been well characterized. Pi, as one of the components of mineral crystals and a signaling molecule that regulates expression of mineralization-related genes, is essential to the mineralization process. In our studies, we discovered a novel function for Pi in this process: Pi is sufficient to induce secretion of matrix vesicles, which support the initiation of mineralization. Furthermore, we determined that this induction is dependent on Pi-induced ERK1/2-activaiton. In our studies, we discovered that the Trps1 transcription factor is involved in Pi signaling. Trps1 has previously been implicated in the development and homeostasis of mineralizing tissues; however its role in the mineralization process is not well understood. Here, we uncovered a context-dependent function for Trps1 in mineralization. Trps1 is important for the initiation of mineralization as it is involved in the secretion of matrix vesicles and expression of key osteogenic proteins such as TNAP and PHOSPHO1 phosphatases and major osteogenic transcription factors Runx2 and Sp7. During the propagation of mineralization, Trps1 must be downregulated for proper expression of Pi regulating genes: Phex, Vdr, Enpp1, and Fam20C. Importantly, we determined that expression of many genes involved in Pi homeostasis and expression of genes regulated by Pi is affected by Trps1, implicating Trps1 in the regulation of Pi and in the Pi signaling pathway. We determined that Trps1 regulates the Pi-induced bi-phasic signaling cascade. Specifically, deficiency of Trps1 caused an absent second activation of ERK1/2 and decreased upregulation of several Pi-responsive genes. In contrast, overexpression of Trps1 resulted in an enhanced and accelerated second activation of ERK1/2 and an increased downregulation of Pi-responsive genes. Furthermore, Trps1 affected expression of the ERK1/2 phosphatase, Dusp6, upon stimulation with Pi. This suggests a function for Trps1 in the ERK1/2 negative feedback loop. Altogether, these studies have found a novel function for Pi in mineralizing cells and have further delineated the role of Trps1 in the mineralization process.

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