The long term objective of this project is to analyze the mechanism by which parathyroid hormone (PTH) controls bone remodeling and stimulates bone resorption. The discovery that PTH does not directly stimulate the osteoclast, but rather increases resorptive activity through actions in other cells (most likely osteoblasts) producing factors acting in the local bone environment to increase osteoclastic activity, has left the mechanisms of PTH action unresolved. Since PTH is one of the most important systemic regulators of bone resorption, knowledge of its mechanism of action is critical to understanding disease states of altered bone resorption such as osteoporosis. Recent literature, including work of the principal investigator, suggest that PTH has a bifunctional mechanism of signal transduction. The PTH-receptor complex couples to adenylate cyclase and increases 3'5' cAMP production, but it also activates the calcium messenger system independent of adenylate cyclase activity.
The specific aims of this project are to characterize stimulation of the calcium messenger by PTH in osteoblasts. The calcium transport mechanisms by which PTH regulates osteoblast cell calcium will be elucidated. These studies will involve isotopic flux studies, microspectrofluorometric determination of cytosolic Ca2+, microinjection studies and patch clamp recordings of single ion channels in osteoblasts. The mechanism of PTH-receptor coupling to stimulation of the calcium messenger system will be analyzed. These studies will involve analysis of PTH receptor binding, stimulation of phospholipase-C and isolation of the PTH receptor coupling to phospholipase-C. Studies in this project will also analyze the stimulation of osteoblast function by PTH, and the role of the calcium messenger system in the stimulation. As a result this project will carefully analyze the control of osteoblast function by PTH, and contribute significantly to our understanding of disease states characterized by increased rates of bone resorption.
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