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(D-Trp 12 ,Tyr 34 )-bPTH(7-34) primarily affected pathways regulating apo-
ptosis, for example, ataxia telangiectasia mutated signaling and p53 signaling;
cell survival, for example, PI3K/AKT signaling; and cell cycle checkpoint
regulation. The effects of (D-Trp 12 ,Tyr 34 )-bPTH(7-34) appeared to reflect
arrestin-dependent signaling, as opposed to antagonismof Gprotein signaling
by endogenous PTH, in that 78%of the significant changes in gene expression
observed inwild-type animals exposed to the biased ligandwere not observed
in identically treated arrestin3 null mice, and there was a high degree of cor-
relation between the pathways analysis performed using the complete list of
(D-Trp 12 ,Tyr 34 )-bPTH(7-34) regulated genes and the list of genes whose
regulation was unique to the wild type background. 44 In contrast, 54% of
genes regulated by hPTH(1-34) in wild-type mice were also regulated in
arrestin3 null mice, and there was much less concordance when the hPTH
(1-34) pathways analysis was repeated using the list of wild-type unique
genes. As expected, most of the effects of intermittent hPTH(1-34) in bone,
including its ability to activate osteoclastic bone resorption, derived from
G protein-dependent signals that do not require arrestin3, so many of its
biological actions were preserved in the arrestin3 null background.
The ultimate expression of ligand action is a change in biological phe-
notype at the tissue or organ level. In bone, PTH directly stimulates bone
forming osteoblasts, promoting deposition of new bone matrix and acceler-
ating the rate of mineralization by increasing both osteoblast number and
activity. At the same time, it accelerates bone turnover by stimulating oste-
oblasts to secrete soluble osteoclast-activating factors, for example, receptor
activator of NF
B ligand, that increase the number and activity of bone
resorbing osteoclasts. The effects of PTH on osteoblasts and osteoclasts
are coupled, such that the net effect of PTH on bone mass is a function
of the magnitude and timing of PTH exposure. 50 Continuous exposure
to excess PTH leads to hypercalcemia and net bone resorption, whereas
intermittent exposure stimulates bone formation in excess of resorption
and a net increase in bone mass. Thus, wild-type mice given daily injections
of hPTH(1-34) for 8 weeks experience a net increase in bone mass. 31,46,47
Trabecular bone volume and cortical thickness increase, as do osteoblast
number, osteoid surface, serum osteocalcin level, and mineral apposition
rate. Reflective of osteoblast-osteoclast coupling, osteoclast numbers also
increase, along with urinary deoxypyrodiniline, a marker of bone resorp-
tion. Twenty-four hour urine calcium excretion rises, reflecting the net
effect of PTH on intestinal calcium absorption and renal tubular calcium
resorption. Interestingly, arrestin3 null mice exhibit an impaired anabolic
k
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