A new study led by researchers at Duke University Medical Center describes similar net bone gain in mice treated with the biased agonist (d-Trp12,Tyr34)-PTH(7–34) (PTH-βarr), which activates β-arrestin signalling but not classical G protein signalling. β-arrestins regulate G protein-coupled receptors both by inhibiting classical signalling and by initiating distinct β-arrestin-mediated signalling. The interplay of these distinct signalling pathways largely determines the cellular consequences of drugs acting at G protein-coupled receptors. In wild-type mice, both PTH-βarr and PTH(1–34), which activates both arrestin and classical pathways, induced anabolic bone formation. In β-arrestin2–null mice, treatment with PTH(1–34) led to a smaller increase in bone mineral density than in wild-type mice and treatment with PTH-βarr had no effect. The β-arrestin pathway leads primarily to trabecular bone formation and does not stimulate bone resorption. The study provides evidence that selective agonism of the β-arrestin pathway can elicit an in vivo response distinct from that elicited by a non-selective agonist, and suggests that such ligands may have therapeutic potential.
The study is published in the inaugural issue of Science Translational Medicine.