Arrestins in Bone - Progress in Molecular Biology and Translational Science - page 331

(MAPK) cascades; the E3 ubiquitin ligase, Mdm2; the cAMP phosphodies-
terases, PDE4D3/5; diacylglycerol kinase; the inhibitor of nuclear factor- k
B, I k B; the Ral-GDP dissociation stimulator, Ral-GDS; and the Ser/Thr
protein phosphatase 2A. 55-57,34,58-61 It is through these interactions that
arrestin-binding confers unique signaling properties upon agonist-occupied
GPCRs, opening up a broad realm of possibilities for manipulating GPCR
signal transduction. 58
A novel feature of at least some arrestin-dependent signals is that they can
be initiated independent of heterotrimericGprotein activation. Downstream
signals emanating from GPCRs in the absence of G protein coupling have
been demonstrated for several different 7TMRs using G protein-uncoupled
receptor mutants and arrestin pathway-selective biased ligands. 37,46,62,63
In bone, the PTH 1 R has been shown to produce arrestin-dependent activa-
tion of ERK1/2 that is temporally distinct fromG protein-dependent mech-
anisms. 63 This ability to dissociate arrestin- and G protein-dependent
PTH 1 R signaling in bone has the potential to impact future therapeutics
in osteoporosis.
3. FUNCTIONAL SELECTIVITY IN BONE
3.1. Regulation of bone metabolism by PTH
PTH is an 84-amino acid peptide hormone that serves as the primary reg-
ulator of bone and mineral metabolism. Expressed principally in the parathy-
roid gland, PTH is excreted in a pulsatile manner and tightly regulates
calcium and phosphate homeostasis. The principle targets of PTH in the
periphery are the kidney and the bone, where its actions promote a rise
in serum calcium. In the kidney, PTH regulates renal tubular calcium
resorption through a well-characterized cAMP-dependent mechanism.
It also regulates renal expression of the 1 a -hydroxyase necessary to convert
25(OH)-vitamin D to its active form 1,25(OH) 2 -vitamin D, which in turn
enhances intestinal calcium absorption.
The physiologic actions of PTH on bone are complex. PTH is known
for both its anabolic effects as well as its catabolic/resorptive effects on bone.
PTH is an important regulator of bone “remodeling,” a lifelong process that
is necessary to maintain structural integrity of the bone microarchitecture
and maintain calcium-phosphorus homeostasis. At the cellular level, PTH
directly stimulates osteoblasts to build bone by increasing osteoblast number
and activity, promoting the deposition of new bone matrix, and accelerating
the rate of mineralization. 64,65 At the same time, PTH stimulates bone