Bone response to intermittent parathyroid hormone is altered in mice null for β-arrestin2

S. L. Ferrari, D. D. Pierroz, V. Glatt, D. S. Goddard, E. N. Bianchi, F. T. Lin, D. Manen, M. L. Bouxsein

Research output: Contribution to journalArticle

110 Scopus citations

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. β-Arrestin2, a G protein-coupled receptor regulatory protein, inhibits PTH-stimulated cAMP accumulation in vitro. Using β-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-κB ligand (RAMKL) 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 μg/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 β-arrestins may specify the activity of intermittent PTH on the skeleton by limiting PTH-induced osteoclastogenesis.

Original languageEnglish (US)
Pages (from-to)1854-1862
Number of pages9
JournalEndocrinology
Volume146
Issue number4
DOIs
StatePublished - Apr 2005
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology

Fingerprint Dive into the research topics of 'Bone response to intermittent parathyroid hormone is altered in mice null for β-arrestin2'. Together they form a unique fingerprint.

  • Cite this

    Ferrari, S. L., Pierroz, D. D., Glatt, V., Goddard, D. S., Bianchi, E. N., Lin, F. T., Manen, D., & Bouxsein, M. L. (2005). Bone response to intermittent parathyroid hormone is altered in mice null for β-arrestin2. Endocrinology, 146(4), 1854-1862. https://doi.org/10.1210/en.2004-1282