Biology Reference
In-Depth Information
that the complex metabolic effects induced by PTH
1
R stimulation are not entirely a con-
sequence of conventional GPCR signaling.
-Arrestins, in addition to their desensitizing
actions, also serve as multifunctional scaffolding proteins linking the PTH
1
R to signaling
molecules independent of classic G protein-mediated second messenger-dependent
pathways. In vitro,
D
-Trp
12
, Tyr
34
-bPTH(7
-
34) [bPTH(7
-
34)], a
b
-arrestin-selective biased
agonist for the PTH
1
R, antagonizes G protein signaling but activates arrestin-dependent
signaling. In vivo, intermittent administration of bPTH(7
-
34) to mice induces anabolic
bone formation independent of classic G protein-coupled signaling mechanisms. While
both the conventional PTH
1
R agonists, PTH(1
-
34) and bPTH(7
-
34), stimulate anabolic
bone formation in mice, the latter does not induce hypercalcemia nor does it increase
markers of bone resorption. This newly recognized ability of
b
-arrestins to serve as signal
transducers for the PTH
1
R independent of classic GPCR signaling represents a novel par-
adigm with therapeutic potential. Exploitation of
b
-arrestin-biased agonism may offer
therapeutic benefit for the treatment of metabolic bone diseases such as osteoporosis
with an improved side effect profile.
b
ABBREVIATIONS
7TMRs
seven transmembrane receptors
BMD
bone mineral density
bPTH(7
-
34)
D
-Trp
12
, Tyr
34
-bPTH(7-34)
DPD
deoxypyrodiniline
GPCR
G protein-coupled receptor
MAPK
mitogen-activated protein kinase
OPG
osteoprotegerin
PTH
parathyroid hormone
PTH
1
R
type I parathyroid hormone receptor
RANKL
receptor activator of NF
k
B ligand
1. INTRODUCTION
Osteoporosis, or lowbone mineral density (BMD), is a significant health
threat amongour aging populationand is associatedwith increased fracture risk,
mortality, and health care cost.
1
It is characterized by deterioration in bone
microarchitecture with resultant need for anabolic therapy.
2
The etiology of
osteoporosis is complex, representing the net imbalance between osteoblast-
mediated bone formation and osteoclast-mediated bone resorption. Currently
employed antiresorptive therapies, such as bisphosphonates, selective estrogen
modulators, supplemental calcium and vitamin D, are not sufficient to regen-
erate lost trabecular bone architecture. Thus, anabolic agents that target
osteoblast-mediated bone formation are needed. Ideally, these therapies would
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