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exocytosis, and cell migration, and impacting more distant processes such as
protein translation and gene transcription.
34
The demonstration that a biased
PTH
1
R agonist selective for the
b
-arrestin pathway can promote anabolic
bone formation without inducing bone resorption or hypercalcemia offers
evidence that biased activators of G protein-independent signaling can pro-
duce
in vivo
biological responses that cannot be attained with conventional
ligands.
15
While no currently used pharmaceuticals are known to possess
unique clinical efficacy based on their ability to bias GPCR signaling in favor
of arrestin-specific transduction, the opportunities for drug development in
osteoporosis are promising.
6. CONCLUSIONS
Pathway-selective PTH analogs have proved to be valuable tools for
determining the contribution of different PTH
1
R signaling pathways to
bone metabolism both
in vitro
and
in vivo
. Recent work using an arrestin
pathway-selective PTH
1
R agonist
in vivo
suggests that activation of arrestin
signaling is sufficient to promote bone formation but is unable to stimulate
bone resorption, meaning that it uncouples the bone forming effects of PTH
on osteoblasts from its previously nondissociable effects on osteoclastic bone
resorption. Although considerable additional work will be required to fully
understand the mechanistic basis of
b
-arrestin signaling in bone and deter-
mine whether arrestin pathway-selective ligands are effective in preclinical
models of metabolic bone disease, the demonstration that an arrestin
pathway-selective biased agonist of the PTH
1
R can accelerate bone forma-
tion
in vivo
offers the best evidence to date that biased activators of
G protein-independent signaling can achieve biological responses that can-
not be attained with nonselective agonists or antagonists.
ACKNOWLEDGMENTS
This work was supported by National Institutes of Health Grants DK64353, and HD043446;
and the Arthritis Foundation.
REFERENCES
Int
.
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