Arrestins in Bone - Progress in Molecular Biology and Translational Science - page 333

was a negative regulator of PTH signaling, intermittent treatment of male
b -arrestin 2 knockout (KO) mice with PTH(1-34) did not increase total
body bone mass and cortical and trabecular bone parameters to the same
degree as wild-type mice, suggesting that arrestin's actions helped to pro-
mote net bone formation. 82 They found that PTH significantly increased
osteoclast number and surface (up to 80%) in KO, but not in WT mice,
suggesting that loss of arrestin-mediated PTH 1 R desensitization, and the
resultant exaggeration of cAMP signaling, leads to unbalanced PTH 1 R sig-
naling and increased osteoclastogenesis.
In contrast, work in estrogen-replete female b -arrestin 2 KO mice
showed that PTH(1-34) had enhanced benefit on total body BMD, trabec-
ular bone architecture, and enhanced cortical effects in KO mice as com-
pared to WT, suggesting that arrestins inhibit the ability of intermittent
PTH to stimulate periosteal bone apposition and endosteal resorption. 83
In females, the lack of b -arrestin 2 led to altered PTH-stimulated osteoblast
activity, characterized by a lower OPG/RANKL mRNA expression ratio,
enhanced osteoclastogenesis, and endosteal bone resorption, 82 but also a
higher bone formation at the periosteum. 83 These findings support the con-
clusion that PTH-mediated osteoblast-osteoclast coupling is cAMP depen-
dent and that sustained cAMP signaling in the absence of an
arrestin-PTH1R interaction promotes bone turnover. 38,82 Further in vitro
and in vivo work demonstrated that b -arrestin 2 decreases PTH-dependent
and -independent bone resorption by modulating RANKL-dependent
osteoclastogenesis. 84
Studies focusing on molecular mechanisms of arrestin signaling in bone
suggest that even conventional PTH 1 R agonists signal by coupling to
arrestins. 15 PTH 1 R activation by PTH(1-34) promotes translocation of
both b -arrestin 1 and b -arrestin 2 to the plasma membrane, association of
the receptor with b -arrestins, internalization of receptor- b -arrestin com-
plexes, and arrestin-dependent activation of ERK1/2. 63,81,85 In vitro ,
PTH(1-34) stimulates ERK1/2 by multiple distinct mechanisms, conven-
tional G protein-dependent pathways that involve PKA and/or PKC, and
a G protein-independent pathway mediated by arrestins. 63,75,77 These dis-
crete G protein-dependent and G protein-independent, b -arrestin-
mediated signaling pathways are temporally distinct. G protein-dependent
ERK1/2 activation is rapid and transient over the course of minutes,
whereas the time course of G protein-independent ERK1/2 activation,
mediated by b -arrestins, is delayed and sustained over the course of hours. 63
Microarray gene expression analysis of osteoblastic cells isolated from WT