Arrestins in Bone - Progress in Molecular Biology and Translational Science - page 327

uncouple bone formation from osteoclast-mediated bone resorption and
improvemineral content and bone qualitywithout contributing to side effects.
Several therapeutic agents, including fluoride, 3-5 humangrowthhormone, 6,7
prostaglandins, 8,9 and parathyroid hormone (PTH) analogs, 10 have been
explored as prospective anabolic treatments. Of these, PTH analogs are the
most efficacious anabolic therapies developed to date.
PTH acts principally through the type I PTH/PTH-related peptide
receptor (PTH 1 R), a classic seven transmembrane G protein-coupled recep-
tor (GPCR). Recent studies have demonstrated that the complex metabolic
effects induced by PTH 1 R stimulation are not entirely a consequence
of conventional GPCR signaling. b -Arrestins, in addition to their GPCR
desensitizing actions, also serve as multifunctional scaffolding proteins
linking the PTH 1 R to signaling molecules independent of the classic
G protein-mediated second messenger-dependent pathways. Presently,
the conventional PTH 1 R agonist, PTH(1-34) (i.e., Forteo ® ), is the only
FDA-approved anabolic approach to stimulate bone formation. Intermittent
treatment with PTH(1-34) promotes osteoblast and osteoclast recruitment
through activation of PTH 1 R with resultant net bone gain. Although effec-
tive in anabolic bone mineralization, its clinical utility is hampered by its
propensity to activate bone resorption and predispose patients to hypercal-
cemia/hypercalcuria with prolonged administration. In addition, long-term
exposure to PTH(1-34) in rats increases osteosarcoma risk, and evidence
links Ca 2 þ -dependent protein kinase C signaling to the initiation and pro-
gression of these PTH-induced osteosarcomas. 11,12 Thus, the development
of PTH receptor agonists that promote osteoblastic bone formation without
stimulating bone resorption may have improved clinical utility for the treat-
ment of osteoporosis. 13-15 A PTH analog that activates b -arrestin-mediated
signaling in the absence of GPCR-dependent signaling shares this desired
pharmacologic profile. 15 The recent identification of b -arrestin-biased ago-
nists may form the basis for pharmacologic agents with enhanced therapeutic
specificity and efficacy. 13-16
2. ARRESTIN SIGNALING: A NEW DIMENSION TO GCPR
SIGNALING IN BONE
2.1. G protein-coupled receptors
Heptahelical GPCRs constitute the largest and the most diverse superfamily
of cell surface receptors, accounting for as many as 1000 discrete receptor
proteins. 17 The superfamily of seven transmembrane receptors (7TMRs)