Parathyroid hormone-related protein (PTHrP) is now understood to be the peptide hormone responsible for the majority of instances of humoral hypercalcemia of malignancy (HHM). It is also clear that the PTHrP gene is expressed in a broad variety of normal tissues, including the skeleton and the kidney, and that it plays normal physiological roles within these tissues. Increasingly, one of these roles is being appreciated to be as a regulator of normal cellular differentiation and proliferation. In addition, the posttranslational processing of PTHrP is rapidly being elucidated. One of the normal secretory forms of the peptide has been shown to be PTHrP(1-36). Despite these recent advances, certain aspects of the pathophysiological picture in HHM remain unclear. Specifically, it is unclear whether and to what extent PTHrP plays a role in renal calcium reabsorption. Second, it is unclear why and how the regulation of plasma 1,25(PH)2 vitamin D differs between patients with HHM and those with primary hyperparathyroidism. Third, it is unclear how and why osteoclast-osteoblast activities, which are coupled in primary hyperparathyroidism, are uncoupled in HHM. Finally, both PTH(1-34) and amino-terminal PTHrP have been shown to be anabolic in terms of their ability to augment skeletal mass in animal models. The first human studies employing hPTHrP(1-36) have recently been completed in the applicant's laboratory. These pilot studies have shown that hPTHrP(1-36) is as potent as hPTH(1-34) as a calcium-mobilizing hormone in human beings. The studies outlined in this proposal are designed to expand these pilot studies. Specifically, they plan: A. To Determine the T1/2, Metabolic Clearance Rate and Site(s) of Clearance of PTHrP(1-36) in Humans; B. To Define Calcium Handling by the Kidney in Response to hPTHrP(1-36) as Compared to hPTH(1-34) in Humans; C. To Study Control of Plasma 1,25(PH)2 by PTHrP(1-36) as compared to hPTH(1-34) in Humans; D. To Determine Whether PTHrP(1-36) has Potential As an Anabolic Therapeutic Agent for Osteoporosis in Humans. These studies should further clarify the pathophysiology underlying HHM. More importantly, they will define the potential of PTHrP as a therapeutic agent in the therapy of osteoporosis.
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