Arrestins in Bone - Progress in Molecular Biology and Translational Science - page 337

Bouxsein reported that intermittent administration of PTH(1-34) increased
bone mass in female b -arrestin 2 null mice but failed to exert an anabolic effect
in male animals. 82,83 The lack of effect in the male b -arrestin 2 / mice was
attributed to the loss of b -arrestin-mediated desensitization of G protein signa-
ling, increased and sustained cyclic AMP, and exaggerated osteoclastogenesis
resulting from an increased RANKL/OPG ratio in the KO animals, 82,83 but
the parallel decrease in bone formation markers suggests that the loss of
b -arrestin 2 might also impair new bone formation. In all, evidence suggests
that b -arrestin 2 is important not only in GCPR desensitization but that
b -arrestin signaling in bone may be important in promoting bone formation.
4.3. Skeletal effects of an arrestin pathway-selective PTH 1 R
agonist
b -Arrestin 2 null mice are impaired in both arrestin-mediated PTH 1 R desen-
sitization and arrestin-mediated signaling. As the two effects cannot be inde-
pendently reconstituted in vivo , it is not possible to determine their
contributions to the actions of PTHon bone by comparing PTH(1-34) effects
in wild-type and b -arrestin 2 null mice. However, the identification of arrestin
pathway-selective biased agonists for the PTH 1 Rhas provided a way to exam-
ine the contributionof arrestin-dependent signaling tobone remodeling in vivo ,
independent of its role in the desensitization of PTH 1 R-mediated G protein
activation. Administering an arrestin pathway-selective PTH analog to wild-
type mice allows one to examine the contribution of b -arrestin-mediated
signaling to skeletal metabolism in the absence of pharmacologic activation
of G protein pathways. The analogous experiment performed in b -arrestin
2 null mice would reveal skeletal effects that might arise from the transient
inhibition of G protein signaling resulting from competitive antagonism of
endogenous PTH signaling. Conversely, administering PTH(1-34) to
b -arrestin 2 null animals allows separation of the effects of G protein signaling
from b -arrestin signaling because PTH(1-34) activates both pathways in wild-
type animals, but only G protein signaling in the KO.
The results of such an experiment, 13 performed in congenic male
b -arrestin 2 null mice and wild-type C57BL/6 controls, are summarized
in Fig. 13.1 . Despite the antagonism of G protein signaling, wild-type ani-
mals treated with bPTH(7-34) exhibited increases in bone formation, asso-
ciated with increased osteoblast number, osteocalcin mRNA expression and
serum osteocalcin level, increased trabecular number and thickness, and
greater bone volume fraction as compared to wild-type animals treated
with PTH(1-34). In b -arrestin 2 null mice, bPTH(7-34) had no significant
effect on bone formation markers, indicating that the changes seen in