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G protein-dependent signaling
Ligand
b -arrestin-dependent signaling
Receptor
GRK
G α
b
-Arrestin
β
γ
Second messengers
Desensitization
Signaling
PTH(1-34) signaling:
Activates both GPCR
and b -arrestin signaling
bPTH(7-34) signaling:
Activates
-arrestin signaling
Acts as an inverse agonist for GPCR
signaling
b
Increases:
Trabecular thickness
Trabecular bone volume
Rate of bone formation
Osteoblast number
Osteoclast activity
Serum osteocalcin
Urine DPD
Urine calcium
Increases:
Trabecular number
Trabecular bone volume
Rate of bone formation
Osteoblast number
Serum osteocalcin
Figure 13.2 Effects of conventional and arrestin pathway-selective biased PTH 1 Ragonists
on bone metabolism in WT and b -arrestin 2 null mice. Stimulation of the PTH 1 Rresultsin
the activation of two distinct signaling pathways: one G protein-mediated and the other
b -arrestin-mediated. Concomitantly, b -arrestins desensitize the G protein-activated
response. The binding of the conventional PTH 1 Ragonist,hPTH(1 - 34), results in the acti-
vation of G protein- and b -arrestin-dependent signaling, whereas bPTH(7 - 34) activates
only the b -arrestin-dependent pathway. bPTH(7 - 34) stimulates anabolic bone formation
through a b -arrestin-dependentmechanism independent of Gprotein activation. Summa-
rized are the effects of PTH(1 - 34) andbPTH(7 - 34) onmarkers of osteoblast-mediatedbone
formation and osteoclast-mediated bone resorption.
process level, this translated into regulation of collagen synthesis, matrix
mineralization, and morphogenic pathways involved in skeletal patterning
and development. On the other hand, bPTH(7-34) primarily affected cell
survival, cell cycle progression, and migration through regulation of gene
clusters associated with PI3K/AKT, p53, phosphatase and tensin homolog,
and ataxia telangiectasia mutated kinase signaling ( Fig. 13.3 ). Confirmatory
in vitro experiments performed using primary calvarial osteoblasts demon-
strated that bPTH(7-34) had direct effects on osteoblast proliferation, anti-
apoptosis, and migration that were absent in b -arrestin 2 null osteoblasts,
suggesting that these responses are dependent on b -arrestin 2 signaling.
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