Epo/EpoR signaling in osteoprogenitor cells is essential for bone homeostasis and Epo-induced bone loss  

作　　者：Martina Rauner Marta Murray Sylvia Thiele Deepika Watts Drorit Neumann Yankel Gabet Lorenz C.Hofbauer Ben Wielockx 

机构地区：[1]Department of Medicine III&Center for Healthy Aging,Technische Universitat Dresden,Dresden,Germany [2]lnstitute for Clinical Chemistry and Laboratory Medicine,Technische Universitat Dresden,Dresden,Germany [3]Department of Cell and Developmental Biology,Sackler Faculty of Medicine,Tel Aviv University,Tel Aviv,Israel [4]Department of Anatomy&Anthropology,Sackler Faculty of Medicine,Tel Aviv University,Tel Aviv,Israel

出　　处：《Bone Research》2021年第4期549-556,共8页骨研究（英文版）

基　　金：This work was supported by grants from the German-lsraeli-Foundation(#1-1433-203.13_2017)to M.R.,D.N.,Y.G.,and B.W.;the DFG priority program pBONE 2084 to M.R.,L.C.H.,and B.W.;the DFG grant RAT 923/10-1 to M.R.;B.W.was further supported by the DFG Heisenberg program.

摘　　要：High erythropoietin(Epo)levels are detrimental to bone health in adult organisms.Adult mice receiving high doses of Epo lose bone mass due to suppressed bone formation and increased bone resorption.In humans,high serum Epo levels are linked to fractures in elderly men.Our earlier studies indicated that Epo modulates osteoblast activity;however,direct evidence that Epo acts via its receptor(EpoR)on osteoblasts in vivo is still missing.Here,we created mice lacking EpoR in osteoprogenitor cells to specifically address this gap.Deletion of EpoR in osteoprogenitors(EpoR:Osx-cre,cKO)starting at 5 weeks of age did not alter red blood cell parameters but increased vertebral bone volume by 25%in 12-week-old female mice.This was associated with low bone turnover.Histological(osteoblast number,bone formation rate)and serum(P1NP,osteocalcin)bone formation parameters were all reduced,as were the number of osteoclasts and TRAP serum level.Differentiation of osteoblast precursors isolated from cKO versus control mice resulted in lower expression of osteoblast marker genes including Runx2,Alp,and Col1a1 on day 21,whereas the mineralization capacity was similar.Moreover,the RANKL70PG ratio,which determines the osteoclast-supporting potential of osteoblasts,was substantially decreased by 50%.Similarly,coculturing cKO osteoblasts with control or cKO osteoclast precursors produced significantly fewer osteoclasts than coculture with control osteoblasts.Finally,exposing female mice to Epo pumps(10 U-d_1)for 4 weeks resulted in trabecular bone loss(-25%)and increased osteoclast numbers(1.7-fold)in control mice only,not in cKO mice.Our data show that EpoR in osteoprogenitors is essential in regulating osteoblast function and osteoblast-mediated osteoclastogenesis via the RANKI70PG axis.Thus,osteogenic Epo/EpoR signaling controls bone mass maintenance and contributes to Epo-induced bone loss.

关 键 词：PROGENITOR HOMEOSTASIS doses 

分 类 号：R68[医药卫生—骨科学]