Beta-Arrestin2 regulates RANKL and ephrins gene expression in response to bone remodeling in mice.
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.
Pierroz
Dominique D
DD
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
A
Bianchi
Estelle N
EN
Glatt
Vaida
V
Capulli
Mattia
M
Rucci
Nadia
N
Cavat
Fanny
F
Rizzoli
René
R
Teti
Anna
A
Bouxsein
Mary L
ML
Ferrari
Serge L
SL
D000818:Animals; D019390:Arrestins / Q000172:deficiency / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D016723:Bone Remodeling / Q000187:drug effects / Q000235:genetics*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002136:Calcium, Dietary / Q000008:administration & dosage / Q000494:pharmacology; D002478:Cells, Cultured; D018920:Coculture Techniques; D036342:Ephrins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000494:pharmacology; D053245:RANK Ligand / Q000235:genetics* / Q000378:metabolism; D036081:Receptors, Eph Family / Q000235:genetics* / Q000378:metabolism; D000071557:beta-Arrestins
D019390:Arrestins; D015415:Biomarkers; D002136:Calcium, Dietary; D036342:Ephrins; D010281:Parathyroid Hormone; D053245:RANK Ligand; D000071557:beta-Arrestins; D036081:Receptors, Eph Family