Arrestins in Bone - Progress in Molecular Biology and Translational Science - page 339

wild-type animals resulted from arrestin signaling and not from inhibition
of PTH 1 R-G protein signaling.
Despite surprising similarity to the anabolic response to hPTH(1-34) in
wild-type animals, it is clear that the arrestin-selective PTH analog does not
elicit the full PTH 1 R signaling response in bone. Unlike PTH(1-34), the
anabolic effect of bPTH(7-34) appeared to be confined to the trabecular
bone compartment. Moreover, selective activation of the b -arrestin 2 path-
way by bPTH(7-34) did not significantly increase any indices of osteoclastic
bone resorption. In wild-type animals, PTH(1-34) stimulated osteoblast/
osteoclast coupling and bone resorption, as evidenced by increases in
RANKL mRNA expression, osteoclast number, and markers of bone
resorption, including urinary calcium excretion and urinary DPD.
b -Arrestin 2 null animals treated with hPTH(1-34) exhibited an exagger-
ated increase in osteoclast number and urine DPD, supporting the conclu-
sion that PTH 1 R-mediated bone resorption is principally mediated via
G protein-dependent signaling pathways that are not activated by the
arrestin-selective PTH analog. These differential effects of PTH(1-34)
and bPTH(7-34) on markers of osteoblast-mediated bone formation and
osteoclast-mediated bone resorption are summarized in Fig. 13.2 .

4.4. hPTH(1 - 34) and bPTH(7 - 34) affect bone mass in vivo

through distinct genomic mechanisms
Although PTH(1-34) and bPTH(7-34) have markedly different in vitro effi-
cacy, both stimulate anabolic bone formation in vivo . To understand how
two PTH 1 R ligands with such different efficacy profiles could both increase
bone mass, a recent study compared their mechanisms of action at the tissue
level using functional genomics. 88 In this study, wild-type and b -arrestin 2
null mice were treated with PTH(1-34) or bPTH(7-34) for 8 weeks, and
gene expression profiles from calvarial bone were analyzed by geneset
enrichment analysis to identify signaling pathway and biological process
gene clusters that were significantly different from vehicle-treated animals.
As shown in Fig. 13.3 , bPTH(7-34) produced a genomic signature with
limited overlap with that produced by the conventional agonist, suggesting
that the two agents have distinctly different mechanisms of action at the tis-
sue level. As expected, PTH(1-34)-treated mice exhibited genome level
changes in pathways classically associated with bone development, remo-
deling, and differentiation, notably Wnt/ b -catenin, bone morphogenic
protein, transforming growth factor-beta (TGF- b ), phosphoinositide
3-kinase/AKT (PI3K/AKT), and MAPK/ERK. 90-92 At the biological