Understanding the mechanisms of the anabolic action of PTH on bone is important both because PTH represents the first anabolic agent useful to treat osteoporosis and because a molecular understanding of PTH's anabolic action will allow the development of even more effective anabolic agents. Our goal here is to use in vivo models to establish the roles of specific "second messenger" pathways responsible for the various actions of PTH that, in sum, result in an increase in bone mass. Understanding of the multiple, specific pathways leading in varying ways to increased bone will make possible the next rational generation of anabolic agents. We also want to understand these mechanisms to understand better the roles of PTH and PTHrP in normal physiology and disease. PTH and PTHrP stimulate both bone formation and bone resorption through activation of the PTH/PTHrP receptor (PTHR1) in cells of the osteoblast lineage. The PTHR1 activates several heterotrimeric G proteins, with Gs and Gq/11 being the best characterized. We will use two genetic models that allow the separation of the actions of these downstream mediators in vivo. One model uses a "knock-in" mouse in which the normal PTHR1 gene has been mutated to selectively disrupt the activation of phospholipase C by the Gq/11 pathway without affecting activation of Gs. The other model is a conditional knockout in which the osterix promoter, active in early osteoblasts, drives the expression of ere recombinase in a way that can be suppressed by tetracycline derivatives ("tet-off"). This ere is used to ablate expression of Gsa postnatally in early cells of the osteoblast lineage through mating with a Gsa floxed mouse and administration of doxycycline for various times. Three models of receptor activation (continuous elevation of PTH through minipump infusion or low calcium diet, and once daily injection of PTH) will be used to determine the roles of distinct pathways in the variety of actions of the PTHR1 on cells of the osteoblast lineage.
Aim 1. Role of PLC signaling in actions of the PTHR1 in bone. Models of intermittent and continuous PTH administration will be used to determine the role of PTHR1 activation of PLC in bone.
Aim 2. Role of Gs signaling in cells of the osteoblast lineage. Comparison of mice missing Gsa in osteoblastic cells with the same mice exposed to continuous or intermittent elevation of PTH levels should allow identification of the responses to activation of the PTHR1 that require Gsalpha
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