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
Search WWH ::




Custom Search