Chapter Thirteen - Arrestins in Bone

Abstract

Parathyroid hormone (PTH) is the principle regulator of calcium-phosphorus metabolism 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 osteoporosis. PTH(1-34) acts principally through the type I PTH/PTH-related peptide receptor (PTH1R), a classic seven transmembrane G protein-coupled receptor (GPCR). Intermittent treatment with PTH(1-34) promotes osteoblast and osteoclast recruitment through activation of PTH1R with resultant net bone gain. Recent studies have demonstrated that the complex metabolic effects induced by PTH1R stimulation are not entirely a consequence of conventional GPCR signaling. β-Arrestins, in addition to their desensitizing actions, also serve as multifunctional scaffolding proteins linking the PTH1R to signaling molecules independent of classic G protein-mediated second messenger-dependent pathways. In vitro, D-Trp(12), Tyr(34)-bPTH(7-34) [bPTH(7-34)], a β-arrestin-selective biased agonist for the PTH1R, antagonizes G protein signaling but activates arrestin-dependent signaling. In vivo, intermittent administration of bPTH(7-34) to mice induces anabolic bone formation independent of classic G protein-coupled signaling mechanisms. While both the conventional PTH1R agonists, PTH(1-34) and bPTH(7-34), stimulate anabolic bone formation in mice, the latter does not induce hypercalcemia nor does it increase markers of bone resorption. This newly recognized ability of β-arrestins to serve as signal transducers for the PTH1R independent of classic GPCR signaling represents a novel paradigm with therapeutic potential. Exploitation of β-arrestin-biased agonism may offer therapeutic benefit for the treatment of metabolic bone diseases such as osteoporosis with an improved side effect profile.