(Taken directly from the application) Parathyroid hormone (PTH), a hormone, and parathyroid hormone-related protein (PTHrP), a paracrine factor, help regulate both bone growth and calcium homeostasis through interactions with a common PTH/PTHrP receptor. This signaling system interacts with other signaling systems including those triggered by Indian hedgehog (Ihh), bone morphogenic proteins (BMPs), and cytokines that activate gp130 to assure normal growth and calcium regulation. Genetically altered mice, including chimeric mice of mixed genetic lineage, will be used to understand the interactions of these signaling systems in vivo.
Aim 1 will study regulation of the growth plate by PTHrP and Ihh through the use of chimeric mice. The role of a feedback loop between PTHrP and Ihh signaling in controlling the rate of chondrocyte differentiation will be assessed, and the role of Ihh in regulating differentiation of adjacent bone cells will be studied. The interactions of BMPs and PTHrP will be analyzed through matings that involve mice transgenic for expression of a constitutively active BMP receptor 1A. The effect of deleting the PTHrP gene from these mice will be analyzed. The lineage relationships of chondrocytes and osteoblasts will be analyzed by studying the fates of genetically marked chondrocytes in chimeric mice.
Aim 2 will analyze the prenatal function of PTH through the study of PTH (-/-) mice. The distinct roles of PTH, PTHrP, and the PTH/PTHrP receptor in bone growth and calcium homeostasis will be analyzed by appropriate matings, followed by analyses of bone structure and parameters of calcium homeostasis.
Aim 3 will study the interactions between PTH/PTHrP receptor signaling and gp130 signaling in stimulating osteoblast lineage cells, which then activate osteoclastogenesis and osteoclast action. Calcium homeostasis will be studied prenatally in gp130 (-/-) mice. The interactions between PTH and gp130 signaling will be studied in chimeric mice and in cell mixing experiments. Together, these studies will define the relationships of important signaling pathways in regulating normal bone development and calcium homeostasis in vivo.
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