β-arrestin-Biased Agonism at the Parathyroid Hormone Receptor Uncouples Bone Formation from Bone Resorption

Parathyroid hormone (PTH) is a principle regulator of bone and calcium metabolism and PTH analogs hold great promise as a therapy for metabolic bone diseases such as osteoporosis. PTH acts principally through the type I PTH/PTH-related peptide receptor (PTH1R), a G protein-coupled receptor (GPCR). GPCRs are a family of seven transmembrane cell surface receptors that share conserved structural, functional, and regulatory properties. Recent studies demonstrate that the complex metabolic effects induced by PTH1R stimulation are not entirely a consequence of conventional GPCR signaling. β-arrestins, in addition to their GPCR desensitizing actions, also serve as multifunctional scaffolding proteins linking the PTH1R to signaling molecules independent of the classic G protein-coupled second messengerdependent pathways. In vitro, D-Trp12,Tyr34-bPTH(7-34) (PTH- arr), a β-arrestin selective biased agonist for the PTH1R, antagonizes receptor-G protein coupling but activates arrestin-dependent signaling. In vivo, intermittent administration of, PTH-βarr to mice, induces anabolic bone formation, completely independent of classic G protein-coupled signaling mechanisms. While both PTH-βarr and the conventional agonist PTH(1-34) stimulate anabolic bone formation in mice, unlike PTH(1-34), which activates G protein coupling, PTH-βarr does not induce hypercalcemia or increase markers of bone resorption. This newly recognized ability of β-arrestins to serve as signal transducers for the PTH1R represents an innovative paradigm of receptor signaling which can be targeted to induce a subset of physiologic responses in bone. Exploitation of β-arrestin biased agonism may offer therapeutic benefit for the treatment of metabolic bone diseases such as osteoporosis.