(Taken from the application): The PTH/PTHrP receptor mediates the actions of both parathyroid hormone (PTH) and PTH-related protein (PTHrP) in bone and other organs. This receptor, found in bone only on cells of the osteoblast lineage, regulates bone formation and the formation and action of osteoclasts. PTH administered continuously causes net bone loss. In contrast, PTH administered by one daily injection increases bone mass. This project seeks to understand the multiple actions of PTH and PTHrP in bone and, thereby, to suggest strategies for most effectively using PTH/PTHrP receptor activation to increase bone mass in people. Previous studies in mice have shown that ablation of the PTH/PTHrP receptor leads to abnormalities in bone structure and calcium homeostasis. These mice die at birth; further, elimination of the receptor from the entire organism makes it impossible to distinguish direct from indirect effects on bone. This project addresses the specific roles of the PTH/PTHrP receptor in bone cells by removing the PTH/PTHrP receptor specifically from cells of the osteoblast lineage or from growth plate chondrocytes.
In Aim I, the cre-loxP strategy will be used to generate mouse lines with the PTH/PTHrP receptor specifically ablated from both mature and less mature cells of the osteoblast lineage, from only mature osteoblasts, or from growth late chondrocytes. The efficiency/specificity of the gene ablations and changes in calcium homeostasis will be characterized.
In Aim II, the effects of removing PTH/PTHrP receptors on osteoblast function will be assessed. Comparisons among the models will reveal the distinct roles of chondrocytes, immature osteoblast-like cells, and osteoblasts on bone responses to activation of the PTH/PTHrP receptor. The specific effects of PTHrP, acting through the PTH/PTHrP receptor, will be determined by studying these lines in a PTH null background.
In Aim III, analogous studies will be performed to determine the role of the PTH/PTHrP receptor in stimulating cells of the osteoclast lineage.
In Aim I V, a strategy for genetically marking cohorts of cells of the osteoblast lineage in vivo and following their fates over time will be used to determine the role of the PTH/PTHrP receptor in determining shifts between distinct pools of osteoblast precursors, osteoblasts, lining cells, and osteoblasts.
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