Arrestins in Bone - Progress in Molecular Biology and Translational Science - page 335

dependent pathway that is unaffected by b -arrestin expression. 63 Similarly,
Bpa 1 -PTHrp(1-36) has been shown to induce sustained G s coupling with-
out promoting b -arrestin-dependent receptor desensitization. 38,39 More
novel, ( D -Trp 12 , Tyr 34 )bPTH(7-34) (bPTH(7-34)) is a PTH analog previ-
ously identified as an inverse agonist for PTH 1 R-G s coupling that is capable
of signaling via a G protein-independent, b -arrestin-mediated pathway as a
b -arrestin pathway-selective biased agonist. 15,63,87
Recent work examining biased agonism at the PTH 1 R demonstrates
that selective activation of G protein-independent arrestin-mediated signal-
ing pathways elicits a physiologic response in bone distinct from that
induced by the conventional PTH 1 R agonist, PTH(1-34). 15,63,88 While
intermittent administration of PTH(1-34) is effective in increasing bone
formation, it is also associated with increases in bone resorption and a pro-
pensity to promote hypercalcemia and hypercalcuria. In contrast, the
arrestin pathway-selective agonist, bPTH(7-34), induces bone formation
independent of classic G protein-coupled signaling mechanisms. Unlike
PTH(1-34), bPTH(7-34) appears to “uncouple” the anabolic effects of
PTH 1 R activation from its catabolic and calcitropic effects. Identification
of b -arrestin pathway-biased agonists like bPTH(7-34) permits the investi-
gation of b -arrestin-mediated signaling pathways in vivo and offers evidence
that arrestin pathway-selective GPCR agonists can elicit potentially benefi-
cial effects in vivo that cannot be achieved using conventional agonist or
antagonist ligands.

4. ARRESTIN SIGNALING EFFECTS IN BONE
4.1. Influence of -arrestin 2 on bone formation and

b

turnover
Both b -arrestin 1 and b -arrestin 2 are expressed in osteoblasts. While the
contributions of b -arrestin 1 to osteoblast function and skeletal metabolism
are not well understood, b -arrestin 2 has been shown to affect bone remo-
deling and the skeletal response to endogenous PTH. 15,82-84

b -Arrestin 2
null mice lack both b -arrestin 2-dependent desensitization of PTH-
stimulated G protein activation and b -arrrestin 2-mediated signaling. In vivo ,
b -arrestin 2 null mice have normal serum calcium levels and no gross
alterations in skeletal morphology or size compared to congenic wild-type
mice. However, the loss of b -arrestin 2 alters underlying bone metabolism.
Circulating levels of endogenous PTH are suppressed in b -arrestin 2 null