β-Arrestin2 regulates RANKL and Ephrins gene expression in response to bone remodeling in mice

Dominique D. Pierroz, Anna Rufo, Estelle N. Biancht, Vaida Glatt, Mattia Capulli, Nadia Rucci, Fanny Cavat, René Rizzoli, Anna Teti, Mary L. Bouxsein, Serge L. Ferrari

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

PTH-stimulated intracellular signaling is regulated by the cytoplasmic adaptor molecule β-arrestin. We reported that the response of cancellous bone to intermittent PTH is reduced in β-arrestin2-/- mice and suggested that β-arrestins could influence the bone mineral balance by controlling RANKL and osteoprotegerin (OPG) gene expression. Here, we study the role of β-arrestin2 on the in vitro development and activity of bone marrow (BM) osteoclasts (OCs) and Ephrins ligand (Efn), and receptor (Eph) mRNA levels in bone in response to PTH and the changes of bone microarchitecture in wildtype (WT) and β-arrestin2-/- mice in models of bone remodeling: a low calcium diet (LoCa) and ovariectomy (OVX). The number of PTH-stimulated OCs was higher in BM cultures from β-arrestin2-/- compared with WT, because of a higher RANKL/OPG mRNA and protein ratio, without directly influencing osteoclast activity. In vivo, high PTH levels induced by LoCa led to greater changes in TRACP5b levels in β-arrestin2-/- compared with WT. LoCa caused a loss of BMD and bone microarchitecture, which was most prominent in β-arrestin2-/-. PTH downregulated Efn and Eph genes in β-arrestin2-/-, but not WT. After OVX, vertebral trabecular bone volume fraction and trabecular number were lower in β-arrestin2-/- compared with WT. Histomor-phometry showed that OC number was higher in OVX-β-arrestin2-/- compared with WT. These results indicate that β-arrestin2 inhibits osteoclastogenesis in vitro, which resulted in decreased bone resorption in vivo by regulating RANKL/OPG production and ephrins mRNAs. As such, β-arrestins should be considered an important mechanism for the control of bone remodeling in response to PTH and estrogen deprivation.

Original languageEnglish (US)
Pages (from-to)775-784
Number of pages10
JournalJournal of Bone and Mineral Research
Volume24
Issue number5
DOIs
StatePublished - May 2009
Externally publishedYes

Keywords

  • Bone remodeling
  • Ephrin
  • Low calcium diet
  • RANKL
  • β-arrestin2

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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