Arrestin’ Osteoporosis

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Osteoblasts creating rudimentary bone tissue

Osteoblasts creating rudimentary bone tissue

Image: Wikimedia - Robert M Hunt

Osteoporosis is the result of an imbalance between bone resorption and bone formation in the constant matrix remodelling process that occurs in healthy bone. Bone remodelling is regulated by parathyroid hormone (PTH) which stimulates bone formation by binding to PTH receptors (PTH1R) on osteoblasts but also indirectly stimulates the formation of new osteoclasts, leading to increased bone resorption. Continuous elevation of PTH in hyperparathyroid disease leads to loss of bone mass and osteoporosis but intermittent elevation with daily injections of a recombinant form of PTH(1-34) results in net bone gain.

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.


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