A beta-arrestin-biased agonist of the parathyroid hormone receptor (PTH1R) promotes bone formation independent of G protein activation

• Published in: Science translational medicine Vol. 1; no. 1; p. 1ra1
• Main Authors: Gesty-Palmer, Diane, Flannery, Pat, Yuan, Ling, Corsino, Leonor, Spurney, Robert, Lefkowitz, Robert J, Luttrell, Louis M
• Format: Journal Article
• Language: English
• Published: United States 07.10.2009
• Subjects: Animals; Arrestins - metabolism; beta-Arrestins; Bone Density; Bone Development - drug effects; GTP-Binding Proteins - metabolism; Male; Mice; Mice, Knockout; Receptor, Parathyroid Hormone, Type 1 - agonists; Signal Transduction
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.3000071

About 40% of the therapeutic agents in use today exert their effects through seven-transmembrane receptors (7TMRs). When activated by ligands, these receptors trigger two pathways that independently transduce signals to the cell: one through heterotrimeric GTP-binding proteins (G proteins) and one through beta-arrestins; so-called biased agonists can selectively activate these distinct pathways. Here, we investigate selective activation of these pathways through the use of a biased agonist for the type 1 parathyroid hormone (PTH)-PTH-related protein receptor (PTH1R), (D-Trp(12),Tyr(34))-PTH(7-34) (PTH-betaarr), which activates beta-arrestin but not classic G protein signaling. In mice, PTH-betaarr induces anabolic bone formation, as does the nonselective agonist PTH(1-34), which activates both mechanisms. In beta-arrestin2-null mice, the increase in bone mineral density evoked by PTH(1-34) is attenuated and that stimulated by PTH-betaarr is ablated. The beta-arrestin2-dependent pathway contributes primarily to trabecular bone formation and does not stimulate bone resorption. These results show that a biased agonist selective for the beta-arrestin pathway can elicit a response in vivo distinct from that elicited by nonselective agonists. Ligands with these properties may form the basis for improved 7TMR-directed pharmacologic agents with enhanced therapeutic specificity.