Grant: Operating Grant

One of the most common causes of disability and death during aging is metabolic bone disease, which includes osteoporosis, bone disease due to cancer, and hyperparathyroidism. We are studying two major hormones, parathyroid hormone (PTH) and PTH related peptide (PTHrP), which regulate normal bone metabolism, but can also contribute to the development and progression of metabolic bone disease. PTH and PTHrP act via a common receptor, the PTH/PTHrP receptor (PTHR1), on target cells, including bone cells. These hormones also regulate calcium metabolism. Calcium itself can act as a hormone by interacting with a calcium sensing receptor (CaSR). CaSR has been identified in several tissues including parathyroid (which produces PTH), kidney and bone. Although continuously high levels of blood PTH, as occur in hyperparathyroidism, can resorb bone (producing "catabolic" effects), activation of CaSR can lower PTH and CaSR activators, called calcimimetics have been developed to control hyperparathyroidism. In contrast to the catabolic effects of continuous PTH, intermittent PTH administration forms bone (an "anabolic" effect) and is therefore used in osteoporosis therapy. Our goal is to understand how PTH and PTHrP interact with calcium acting via CaSR in producing anabolic and catabolic effects on bone. We have developed genetically modified mice to study the roles of these factors in regulating bone, and will now utilize these models to examine how PTH exerts an anabolic effect on bone in the absence of CaSR, to determine if CaSR activation can influence bone in the absence of PTH, and to examine how CaSR-induced skeletal increases in PTHrP impact on its bone-regulating actions. These studies should improve our understanding of how to better prevent important and common metabolic bone diseases where bone resorption is a feature, and how to develop improved anabolic therapies for diseases of the skeleton.