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

A biased agonist binds to the seven-transmembrane parathyroid hormone receptor to trigger certain downstream effects but not others, potentially avoiding undesirable side effects. Building Better Bones What do β-blockers, antihistamines, and opiate pain drugs have in common? All act on constituents of the ~1000-member family of seven-transmembrane receptors (7TMRs). Arrayed on the surfaces of all cells in the body, these diverse proteins regulate myriad critical functions, including heart beat, immune response, secretion, and stomach acid production. Almost half of today’s prescribed drugs act to modulate the action of members of this huge family of receptors. When bound by their natural trigger—or a drug—these receptors activate two downstream cellular pathways: one mediated by G proteins and the other, discovered in the last 10 years, mediated by a small protein called β-arrestin, which can both terminate G protein–dependent signaling and activate other cellular processes. Finding the β-arrestin pathway raised the possibility that one could discover drugs that modulate the two signaling pathways independently and so produce better outcomes for patients, with fewer side effects. Gesty-Palmer et al. now show that a so-called biased agonist, PTH-βarr, selectively activates the β-arrestin (but not the G protein) pathway in mouse bone cells by binding to the 7TMR for parathyroid hormone (PTH), a key regulator of bone growth. By stimulating only the β-arrestin arm of the PTH-activated responses, PTH-βarr leads to bone growth in living mice without simultaneous bone degradation, which usually occurs through the G protein–linked pathway. Bone is remodeled throughout life, being continuously broken down by one type of bone cell (osteoclasts) and then rebuilt by another (osteoblasts). One regulator of the balance between the two processes is PTH. When this normal equilibrium goes awry, such that there is more bone destruction than production, bones become structurally weak, and bone diseases such as osteoporosis result. Patients with osteoporosis often are treated with bisphosphonate drugs, which prevent bone loss by binding to the calcium hydroxyapatite in bone and inhibiting the bone-degrading osteoclasts. Although bisphosphonates decrease the risk of fracture, the microarchitecture of bisphosphonate-induced bone is not normal, and long-term use can lead to adynamic bone fractures. Better bone microstructure can be built by daily injections of a fragment of PTH, which directly stimulates osteoblasts, but the PTH fragment also indirectly stimulates osteoclasts and must be injected daily to prevent the osteoclast-driven breakdown from reversing the induced bone growth. Because its effects are tilted more toward anabolic bone growth without simultaneous catabolism, PTH-βarr or similar biased agonists may prove to be superior treatments for osteoporosis. The results in Gesty-Palmer et al. illustrate that, by activating exclusively the β-arrestin pathway downstream of the PTH receptor, a biased agonist can stimulate a desirable physiological outcome (bone growth) while minimizing an undesirable effect (bone degradation). The benefits of biased agonists with differential signaling properties may extend to any therapeutic agent that acts through a 7TMR. 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.