CONSTITUTIVELY ACTIVE PTH/PTHRP RECEPTORS IN OSTEOBLAST

Massachusetts General Hospital, Boston MA

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Abstract

DESCRIPTION: (Taken from the application): PTH is an important physiological regulator of bone turnover and calcium homeostasis. Despite the considerable number of studies, there are still many unanswered questions about the mechanism of action of PTH in bone. In vitro and in vivo studies have demonstrated the crucial role of the PTH/PTHrP receptor in mediating PTH actions in bone. Recently, we have developed a transgenic mouse model (CL), in which a constitutively active human PTH/PTHrP receptor was expressed under the control of the mouse alpha1 (I) collagen gene promoter. We will take advantage of this unique model to dissect out some of the mechanisms underlying the anabolic and catabolic actions of PTH in bone. By breeding CL mice with transgenic mice in which bone resorption is impaired by systemic overexpression of Osteoprotegerin (OPG), we will study whether bone resorption is a prerequisite for PTH/PTHrP receptor-induced bone formation (Specific Aim I). By comparing the phenotype of transgenic mice (OS) that express a constitutively active human PTH/PTHrP receptor under the control of the mouse osteocalcin gene promoter to the phenotype of CL animals, we will determine the role of the PTH/PTHrP receptor on osteoblasts/stromal cells of varying degrees of differentiation (Specific Aim II). By studying differentiation and activity of osteoprogenitor cells isolated from the bone marrow and the periosteum of CL mutant mice and then transplanted into immunodeficient mice, we will evaluate the role of the microenvironment in generating the different responsiveness of these cells to activation of the PTH/PTHrP receptor (Specific Aim III). By analyzing with microarray assays RNA extracted from osteoprogenitor cells and more mature osteoblasts isolated from both CL mutant mice and wild-type littermates, we will systematically study known and unknown genes that are regulated by activation of the PTH/PTHrP receptor in cells of the osteoblast lineage (Specific Aim IV).