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PMID: 19113915 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Beta-Arrestin2 regulates RANKL and ephrins gene expression in response to bone remodeling in mice.

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research ·Vol. 24 ·No. 5 ·2009-05-00 ·Pages 775-84

Pierroz DD, Rufo A, Bianchi EN, Glatt V, Capulli M, Rucci N, Cavat F, Rizzoli R, Teti A, Bouxsein ML, Ferrari SL

Abstract

PTH-stimulated intracellular signaling is regulated by the cytoplasmic adaptor molecule beta-arrestin. We reported that the response of cancellous bone to intermittent PTH is reduced in beta-arrestin2(-/-) mice and suggested that beta-arrestins could influence the bone mineral balance by controlling RANKL and osteoprotegerin (OPG) gene expression. Here, we study the role of beta-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 beta-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 beta-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 beta-arrestin2(-/-) compared with WT. LoCa caused a loss of BMD and bone microarchitecture, which was most prominent in beta-arrestin2(-/-). PTH downregulated Efn and Eph genes in beta-arrestin2(-/-), but not WT. After OVX, vertebral trabecular bone volume fraction and trabecular number were lower in beta-arrestin2(-/-) compared with WT. Histomorphometry showed that OC number was higher in OVX-beta-arrestin2(-/-) compared with WT. These results indicate that beta-arrestin2 inhibits osteoclastogenesis in vitro, which resulted in decreased bone resorption in vivo by regulating RANKL/OPG production and ephrins mRNAs. As such, beta-arrestins should be considered an important mechanism for the control of bone remodeling in response to PTH and estrogen deprivation.

MeSH Terms
Animals Arrestins/deficiency,metabolism Biomarkers/metabolism Bone Marrow Cells/drug effects,metabolism Bone Remodeling/drug effects,genetics Bone and Bones/drug effects,metabolism,pathology Calcium, Dietary/administration & dosage,pharmacology Cells, Cultured Coculture Techniques Ephrins/genetics,metabolism Gene Expression Regulation/drug effects Gene Silencing/drug effects Mice Organ Size/drug effects Osteoblasts/drug effects,metabolism Osteoclasts/drug effects,metabolism Osteogenesis/drug effects Ovariectomy Parathyroid Hormone/pharmacology RANK Ligand/genetics,metabolism Receptors, Eph Family/genetics,metabolism beta-Arrestins
Chemicals
Arrestins Biomarkers Calcium, Dietary Ephrins Parathyroid Hormone RANK Ligand beta-Arrestins Receptors, Eph Family
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Pierroz Dominique D
Service of Bone Diseases, Department of Rehabilitation and Geriatrics, WHO Center for Osteoporosis Prevention, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland. Dominique.Pierroz@unige.ch
Rufo Anna
Bianchi Estelle N
Glatt Vaida
Capulli Mattia
Rucci Nadia
Cavat Fanny
Rizzoli René
Teti Anna
Bouxsein Mary L
Ferrari Serge L
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Article Info
Journal
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Abbr.
J Bone Miner Res
ISSN
1523-4681
DOI
10.1359/jbmr.081237
Email
dominique.pierroz@unige.ch
Published
2009-05-00
Pages
775-84
Language
English
Region
United States
NLM ID
8610640
PMCID
PMC2672203
Subset
IM
Grants
NIAMS NIH HHS · R01 AR049265 · United States
NIAMS NIH HHS · R55 AR049265 · United States
NCRR NIH HHS · S10 RR017868 · United States
NIAMS NIH HHS · AR-049265 · United States
External Links
PubMed source DOI: 10.1359/jbmr.081237 PMC Full Text View journal details
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