MOLECULAR REGULATION OF THE PARATHYROID HORMONE RECEPTOR
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The hormonal regulation of bone at the cellular level is a critical component of physiologic bone remodeling and a central component in the pathophysiology of conditions such as osteoporosis, cancer-associated hypercalcemia, and hyperparathyroidism. Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) are calcium-regulating hormones with endocrine, paracrine and autocrine actions in bone. PTH and PTHrP stimulate bone resorption and formation and bind to the same cell surface receptor on osteoblasts. Although their functions have been an area of intensive investigation, little is known regarding the molecular mechanisms regulating the cell surface receptor which is necessary for PTH/PTHrP actions on osteoblasts. Based on data from previous investigations and preliminary data in progress there is convincing evidence that the differentiation of pre-osteoblastic cells into active matrix-producing osteoblasts likely depends on regulation by PTH/PTHrP and consequently, the presence of the PTH/PTHrP receptor. The central hypothesis is that PTH/PTHrP receptor levels and activity are regulated as osteoblast precursors progress through their differentiation program, and, furthermore, that osteoblasts are dependent upon the PTH/PTHrP receptor for normal differentiation. Studies will focus on the relationship between osteoblast differentiation and expression of the PTH/PTHrtP receptor and determine mechanisms through which PTH and PTHrP promote osteoblastic differentiation. The specific aims of these studies are; 1) to determine the effects of osteoblast differentiation on mRNA expression and ligand binding of the PTH/PTHrP receptor, 2) to confirm that the PTH/PTHrP receptor is necessary for normal differentiation of osteoblasts, and 3) to establish that anabolic actions of PTH/PTHrP are dependent on the PTH/PTHrP receptor. These studies will provide vital information regarding the hormonal regulation of osteoblast differentiation and enhance our understanding of bone disorders at the cellular and molecular level. This information to be clinically useful in designing preventive and treatment strategies for localized and systemic bone diseases.
