Arrestins in Bone - Progress in Molecular Biology and Translational Science - page 332

resorption by indirectly recruiting osteoclasts. Because they lack PTH
receptors, osteoclasts respond to factors, such as receptor activator of NF k B
ligand (RANKL) and osteoprotegerin (OPG), secreted by osteoblasts in
response to PTH. Osteoclastic activity is triggered via the osteoblasts'
surface-bound RANKL activating the osteoclasts' surface-bound receptor
activator of NF k B, OPG works to inhibit osteoclastogenesis by serving as
a decoy receptor for RANKL.
The net effect of PTH on bone density is dependent upon the kinetics
of receptor activation and the intrinsic concentrations of OPG and
RANKL. 66,10 Intermittent exposure to PTH produces a net increase in
bone formation, while continuous exposure produces a net decrease in bone
formation and possible hypercalcemia. 64,10,67,68 The underlying molecular
mechanisms contributing to these opposing physiologic effects are not well
understood.
3.2. PTH receptor-mediated G protein signaling in bone
PTH acts principally through the PTH 1 R, a class II GPCR that is highly
expressed in the kidney and the bone. Most of its known effects are mediated
by classic G protein signaling mechanisms, including G s -mediated activation
of adenylyl cyclase, resulting in cAMP production and PKA activation, and
G q/11 -mediated activation of phospholipase-C b , leading to inositol-1,4,5-
trisphosphate production, calcium mobilization, and PKC activation. 69-73
In renal tubular epithelium, PDZ domain-mediated binding of Na þ /H þ
exchanger regulatory factor 2 to the PTH 1 R C-terminus permits the recep-
tor to engage G i/o proteins, leading to inhibition of adenylyl cyclase while
simultaneously enhancing receptor coupling to G q/11. 74 PTH also activates
the ERK1/2 MAPK cascade through both PKA and PKC in a cell-specific
and G protein-dependent manner. 75-77 PTH-stimulated MAPK pathway
activation has been shown to have proliferative and differentiative effects
in bone. 78,79
3.3. PTH receptor-mediated arrestin signaling in bone
Arrestin function in bone was first described in an osteoblastic cell line
(UMR 106-H5), where b -arrestin 2 was found to be involved in PTH 1 R
desensitization. 80 Further studies by Ferrari and Bouxsein showed that the
PTH 1 R and b -arrestin 2 colocalized intracellularly upon receptor activation
and that b -arrestin 2 promoted endocytosis of the PTH 1 R and attenuated
PTH-stimulated cAMP accumulation. 81 Despite finding that b -arrestin 2