Arrestin Pathways as Drug Targets - Progress in Molecular Biology and Translational Science - page 466

response to hPTH(1-34), with blunted increases in trabecular bone volume
and no change in cortical thickness. 31,51
Traditionally, the actions of PTH in bone have been attributed to
cAMP-G s signaling, 52 so the expectation would be that systemic administra-
tion of a ligand like (D-Trp 12 ,Tyr 34 )-bPTH(7-34), which antagonizes
PTH 1 R-G s coupling, would at best have no effect on bone mass. Indeed,
treatment of rats with the neutral PTH 1 R antagonist, hPTH(7-34)
( Fig. 18.1 B), reportedly does not affect bone mass in rats. 53 Paradoxically,
wild-type mice treated with (D-Trp 12 ,Tyr 34 )-bPTH(7-34) exhibited
increased bone formation with greater trabecular bone volume and
increased osteoblast number, osteoid surface, serum osteocalcin, and mineral
apposition. Although similar to the response to hPTH(1-34), some differ-
ences were apparent. In trabecular bone, (D-Trp 12 ,Tyr 34 )-bPTH(7-34) pri-
marily increased trabecular number, while hPTH(1-34) had larger effects on
trabecular thickness. More dramatically, (D-Trp 12 ,Tyr 34 )-bPTH(7-34) had
no effect on osteoclast number or bone turnover markers. All responses to
(D-Trp 12 ,Tyr 34 )-bPTH(7-34) were either absent or reversed in arrestin3
null mice, suggesting that in vivo , arrestin signaling is sufficient to promote
osteoblastic bone formation but not to stimulate bone resorption. The key to
this unexpected phenotype apparently lies in the ability of (D-Trp 12 ,Tyr 34 )-
bPTH(7-34) to expand the osteoblast pool through arrestin-dependent cell
cycle regulation and anti-apoptotic signaling, while “uncoupling” the
PTH 1 R from G s -cAMP dependent activation of osteoclasts. 31,44
Other evidence that unexpected in vivo phenotypes may emerge from
systemic administration of arrestin-selective ligands comes from the study
of biased AT 1A receptor ligands in heart failure. In vitro , SII produces positive
inotropic and lusitropic effects on isolated murine cardiomyocytes. 42
Another arrestin pathway-selective AT 1A receptor agonist, TRV120027
[Sar-Arg-Val-Tyr-Ile-His-Pro-(D)-Ala-OH], which stimulates arrestin-
dependent activation of Src, ERK1/2, and endothelial nitric-oxide synthase
in vitro , similarly improves cardiomyocyte contractility. 54 Administration of
TRV120027 to rats reduces mean arterial blood pressure, as do the non-
peptide AT 1A receptor antagonists losartan and telmisartan, but unlike the
neutral antagonists, which decrease cardiac performance, TRV120027
increases cardiac performance and preserves cardiac stroke volume. Unex-
pectedly, however, the principal effect of SII in a murine model of heart fail-
ure appears to be to promote aldosterone production via arrestin2- and
ERK1/2-dependent upregulation of steroidogenic acute regulatory protein
(StAR), a steroid transport protein that

is the rate-limiting step in