Arrestins in Bone - Progress in Molecular Biology and Translational Science - page 336

mice, 89 possibly a compensatory mechanism to maintain physiologic cal-
cium homeostasis in the setting of impaired PTH 1 R desensitization.
b -Arrestin 2 null mice exhibit higher basal rates of bone turnover compared
to wild-type mice. Osteoid surface and osteocalcin mRNA levels are
increased, consistent with an overall increase in the rate of bone formation,
while at the same time bone resorption is accelerated, as evidenced by
increased osteoclast surface and bone turnover markers such as urine
deoxypyrodiniline (DPD) excretion. 15,84
Although the trabecular bone mineral densities and bone volume frac-
tion of b -arrestin 2 null and wild-type mice are comparable, the KOs show
microarchitectural differences, such as increased trabecular thickness and
decreased trabecular number. These differences likely represent the net
effect of increased bone formation that is offset by accelerated bone resorp-
tion. Collectively, these findings clearly demonstrate that b -arrestin 2 is not
required for skeletal patterning and development and suggest that a major
function in bone is to dampen heterotrimeric G protein signaling, consistent
with its ubiquitous role in GPCR desensitization.
4.2. The effect of PTH arrestin signaling: Beyond
desensitization
When one overrides compensatory physiologic mechanisms by exposing
b -arrestin 2 null mice to pharmacologic levels of intermittent PTH
(1-34), differences emerge that suggest arrestins in bone may play roles
beyond GPCR desensitization. 13,15,82,84 In wild-type animals, intermittent
administration of PTH(1-34) produces the expected increases in indices of
bone formation including increased osteoblast number and osteoid surface,
increased osteocalcin mRNA, and increased serum osteocalcin level. PTH
(1-34) also produces the expected increase in osteoclast activity marked by
increased RANKL mRNA expression, increased osteoclast surface, and
increased urine DPD excretion. Together, these opposing responses reflect
the PTH 1 R-dependent coupling of osteoblastic bone formation to osteo-
clastic bone resorption. The net effect of intermittent PTH(1-34) is
increased bone formation, as evidenced by an increase in trabecular bone
volume, trabecular number, and trabecular thickness within cancellous
bone. Additional increases in periosteal circumference and cortical thickness
in the femur indicate a net increase in cortical bone formation.
The response to intermittent PTH(1-34) in b -arrestin 2 null mice is more
complex. b -Arrestin 2 null mice treated with PTH(1-34) demonstrate atten-
uated bone formation at trabecular and endocortical bone surfaces as well as
increased markers of bone resorption. 15 As previously discussed, Ferrari and