Arrestins in Bone - Progress in Molecular Biology and Translational Science - page 342

Consistent with previous studies, 13,38,83 PTH(1-34) produced larger
increases in RANKL mRNA expression than bPTH(7-34). As b -arrestin-2
null mice have higher osteoclast numbers and activity and an exaggerated
osteoclastic response to PTH(1-34) compared to wild-type mice, these
results confirm that PTH 1 R-mediated bone resorption requires G protein
signaling that is normally restrained by arrestin-mediated desensitization.
Thus, both facets of arrestin action, desensitization and signaling, contribute
to PTH 1 R actions in bone. The data suggest that the arrestin pathway-
specific ligand increases matrix synthesis and mineralization in vivo by pro-
moting osteoblast survival and expansion of the osteoblast pool without
simultaneously accelerating bone turnover, whereas the conventional ago-
nist stimulates osteoblast differentiation and function that is coupled with
recruitment of osteoclasts. Both ligands increase bone mass, but the anabolic
effects are achieved through substantially different mechanisms of action.
4.5. Arrestin pathway-selectivity as a strategy for drug design
The finding that bPTH(7-34) can uncouple bone formation from bone
resorption offers compelling evidence that arrestin pathway-selective
GPCR ligands may possess clinically useful properties distinct from conven-
tional agonists or antagonists. The phenomenon of functional selectivity
presents the opportunity to develop drugs that target GPCRs with unique
biologic actions as well as improved specificity and efficacy. Ligands that
direct signaling toward individual G protein pathways may prove useful
in a variety of settings. G protein-selective ligands that signal without pro-
ducing arrestin-dependent desensitization have seemingly obvious applica-
tions, for example, targeting opioid receptors for the management of chronic
pain. 93 Settings where arrestin pathway-selectivity could prove valuable are
perhaps less obvious, as our present understanding of the physiological roles
of arrestin signaling in vivo is incomplete. 34 Regardless, current data suggest
that functional selectivity can be exploited to change the quality of GPCR
efficacy in vivo and may prove a useful strategy in future drug development.
5. PERSPECTIVES AND FUTURE DIRECTIONS
The true scope of physiologically relevant arrestin signaling remains
largely unknown. However, a growing literature supports the concept that
arrestin-bound effectors perform numerous functions, among them enhanc-
ing second messenger degradation, regulating cytoskeletal dynamics con-
trolling GPCR endocytosis, postendocytic receptor trafficking, vesicle