title: β-arrestin-biased agonism at the parathyroid hormone receptor uncouples bone formation from bone resorption.
abstract: 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 IPTH/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 messenger-dependent pathways. In vitro, D-Trp(12),Tyr(34)-bPTH(7-34) (PTH-βarr), 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.
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, Duke University Medical, Center, Durham, NC 27710, USA.
authors.forename: Brittany N
authors.initials: BN
authors.lastname: Bohinc
authors.forename: Diane
authors.initials: D
authors.lastname: Gesty-Palmer
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism / Q000494:pharmacology*; D001862:Bone Resorption / Q000209:etiology / Q000378:metabolism*; D054333:Drug Partial Agonism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D010012:Osteogenesis / Q000187:drug effects*; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000819:agonists* / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D044168:Receptor, Parathyroid Hormone, Type 1; D000071557:beta-Arrestins