Abstract:
:Intermittent PTH administration increases bone turnover, resulting in net anabolic effects on bone. These effects are primarily mediated by intracellular cAMP signaling. However, the molecular mechanisms that regulate PTH activity in bone remain incompletely understood. beta-Arrestin2, a G protein-coupled receptor regulatory protein, inhibits PTH-stimulated cAMP accumulation in vitro. Using beta-arrestin2(-/-) (KO) and wild-type (WT) mice, we investigated the response to PTH in primary osteoblasts (POB) and the effects of intermittent PTH administration on bone mass and microarchitecture in vivo. Compared with that in WT mice, PTH-stimulated intracellular cAMP was increased and sustained in KO POB. Intermittent exposure of POB to PTH significantly decreased the ratio of osteoprotegerin (OPG) receptor activator of nuclear factor-kappaB ligand (RANKL) mRNA expression in KO POB, whereas it increased this ratio in WT POB. Total body bone mass and cortical and trabecular bone parameters were 5-10% lower in male KO mice compared with WT, and these differences were magnified upon in vivo administration of intermittent PTH (80 mug/kg.d) for 1 month. Thus, PTH significantly increased total body bone mineral content as well as vertebral trabecular bone volume and thickness in WT, but not KO mice. The anabolic response to PTH in cortical bone was also slightly more pronounced in WT than KO mice. Histomorphometry indicated that PTH prominently stimulated indexes of bone formation in both WT and KO mice, whereas it significantly increased indexes of bone resorption (i.e. osteoclast number and surface) in KO mice only. In conclusion, these results suggest that beta-arrestins may specify the activity of intermittent PTH on the skeleton by limiting PTH-induced osteoclastogenesis.
journal_name
Endocrinologyjournal_title
Endocrinologyauthors
Ferrari SL,Pierroz DD,Glatt V,Goddard DS,Bianchi EN,Lin FT,Manen D,Bouxsein MLdoi
10.1210/en.2004-1282subject
Has Abstractpub_date
2005-04-01 00:00:00pages
1854-62issue
4eissn
0013-7227issn
1945-7170pii
en.2004-1282journal_volume
146pub_type
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