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REGULATION OF PTH ACTIVITY IN BONE BY BETA-ARRESTIN


Biography

Overview
Parathyroid hormone (PTH) is a major regulator of mineral homeostasis and bone metabolism. Intermittent PTH therapy is approved for treatment of osteoporosis, yet the cellular mechanisms underlying the biologic effects of PTH are incompletely understood, including the molecular basis for the observation that low-dose, intermittent administration of PTH elicits net bone formation, whereas continuous administration of high-dose PTH causes predominantly bone resorption. The actions of PTH on bone and kidney are mediated by the Type 1 PTH receptor (PTH1R), a G protein-coupled receptor (GPCR).beta-arrestins (1 and 2) are cytoplasmic molecules that regulate GPCR activity. We previously reported that arrestins inhibit PTH-stimulated cAMP signaling and trigger cellular internalization of PTH and its receptor in vitro. Thus, our primary hypothesis is that beta-arrestin2 is a key modulator of the activity of PTH in bone. In support of this hypothesis, our preliminary data indicate that compared to wild-type (WT) mice, beta-arrestin2 null (beta-arr2-/-) mice have reduced bone mass and architecture, and importantly, an altered skeletal response to intermittent PTH that is characterized by increased bone resorption leading to decreased net anabolic effects on trabecular bone. Moreover, compared to WT, osteoblasts from beta-arr2-/- mice exhibit increased and sustained cAMP signaling in response to PTH. Thus, to further explore the role of beta-arr2 in mediating the skeletal response to PTH we will pursue three specific aims: 1) Determine the skeletal response of ovariectomized beta-arr2-/- and WT mice to intermittent PTH, thereby allowing examination of the role of beta-arr2 in the context of high bone remodeling induced by estrogen deficiency; 2) Investigate the arrestin-mediated regluation of PTH-stimulated intracellular signaling and gene expression by comparing primary osteoblastic cells from beta-arr2-/- and WT mice; and 3) Determine the skeletal response to intermittent and continuous PTH administration in transgenic mice with targeted overexpression of beta-arrestin2 in well-differentiated osteoblasts (OC-beta-arr2-GFP-Tg+). In summary, the overall goal of this project is to improve our understanding of the mechanisms regulating the activity of PTH in bone. By conducting complementary in vivo and in vitro experiments in mice deficient for beta-arrestin2 and in mice overexpressing beta-arrestin-2 in mature osteoblasts, we will provide novel insights into the mechanisms that underlie the distinct skeletal response to intermittent versus continuous PTH administration. Information gained from the proposed studies will be instrumental for developing new PTH1R ligands with improved signaling and biologic activity profiles for treatment of osteoporosis and other metabolic bone disorders.
R01AR049265
BOUXSEIN, MARY L

Time
2005-07-01
2009-10-31
Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.