Grant: Project 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, hyperparathyroidism, and osteomalacia. We are studying three major hormones, parathyroid hormone (PTH), PTH related peptide (PTHrP), and vitamin D which regulate normal bone metabolism, but can also contribute to the development and progression of metabolic bone disease. Calcium itself can act as a hormone by interacting with a calcium sensing receptor (CaSR), which has been identified in several tissues including parathyroid (which produces PTH), kidney and bone. Activation of CaSR can lower PTH and CaSR activators, called calcimimetics have been developed to control hyperparathyroidism. Although continuously high levels of blood PTH, as occur in hyperparathyroidism, can destroy (resorb) bone (producing "catabolic" effects), in contrast, intermittent PTH administration forms bone (an "anabolic" effect) and is therefore used in osteoporosis therapy. Vitamin D has also been reported to have both anabolic and catabolic effects on bone but the precise mechanism is also unclear. Wnt is a growth factor which is a potent stimulator of bone formation, and can be inhibited by a bone-derived protein called sclerostin. Our goal is to understand how PTH, PTHrP and vitamin D exert their anabolic effects on bone. We will use genetically modified mouse models to examine the ways PTH and PTHrP act to form bone, determine if CaSR activation can influence the anabolic effects of PTH on bone, and determine if vitamin D stimulates bone by interacting with sclerostin. These studies should improve our understanding of how these hormones influence bone, and how to develop improved anabolic therapies for important diseases of the skeleton.