Arrestins in Bone - Progress in Molecular Biology and Translational Science - page 325

CHAPTER THIRTEEN

Arrestins in Bone

,

Brittany N. Bohinc * , Diane Gesty-Palmer *

†
* Department of Medicine, Division of Endocrinology and Metabolism, Duke University Medical Center,
Durham, North Carolina, USA
† Parexel International, Research Triangle Park, Durham, North Carolina, USA

Contents
1. Introduction 336

2. Arrestin Signaling: A New Dimension to GCPR Signaling in Bone 337

2.1 G protein-coupled receptors 337

2.2 Multiple dimensions of GPCR signaling 339

2.3 Functional selectivity 339

2.4 Arrestins as mediators of GPCR signaling 340

3. Functional Selectivity in Bone 341

3.1 Regulation of bone metabolism by PTH 341

3.2 PTH receptor-mediated G protein signaling in bone 342

3.3 PTH receptor-mediated arrestin signaling in bone 342

3.4 Biased agonism at the PTH receptor 344

4. Arrestin Signaling Effects in Bone 345

4.1 Influence of b -arrestin 2 on bone formation and turnover 345

4.2 The effect of PTH arrestin signaling: Beyond desensitization 346

4.3 Skeletal effects of an arrestin pathway-selective PTH 1 R agonist 347

4.4 hPTH(1 - 34) and bPTH(7 - 34) affect bone mass in vivo through distinct

genomic mechanisms 349

4.5 Arrestin pathway-selectivity as a strategy for drug design 352

5. Perspectives and Future Directions 352

6. Conclusions 353

Acknowledgments 353

References 353

Abstract
Parathyroid hormone (PTH) is the principle regulator of calcium - phosphorus metabo-
lism and bone turnover. Because of its central role in bone remodeling, recombinant
human PTH (i.e., Forteo ® ; PTH(1 - 34)) has been developed for the treatment of osteo-
porosis. PTH(1 - 34) acts principally through the type I PTH/PTH-related peptide receptor
(PTH 1 R), a classic seven transmembrane G protein-coupled receptor (GPCR). Intermittent
treatment with PTH(1 - 34) promotes osteoblast and osteoclast recruitment through
activation of PTH 1 R with resultant net bone gain. Recent studies have demonstrated