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Keywords:

  • β-arrestin2;
  • RANKL;
  • ephrin;
  • low calcium diet;
  • bone remodeling

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. Histomorphometry 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.