Research ArticleDrug Discovery

A β-Arrestin–Biased Agonist of the Parathyroid Hormone Receptor (PTH1R) Promotes Bone Formation Independent of G Protein Activation

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Science Translational Medicine  07 Oct 2009:
Vol. 1, Issue 1, pp. 1ra1
DOI: 10.1126/scitranslmed.3000071

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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 β-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-Trp12,Tyr34)-PTH(7–34) (PTH-βarr), which activates β-arrestin but not classic G protein signaling. In mice, PTH-βarr induces anabolic bone formation, as does the nonselective agonist PTH(1–34), which activates both mechanisms. In β-arrestin2–null mice, the increase in bone mineral density evoked by PTH(1–34) is attenuated and that stimulated by PTH-βarr is ablated. The β-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 β-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.


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