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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Martina Rauner - , Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Marta Murray - , Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Sylvia Thiele - , Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Deepika Watts - , Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Drorit Neumann - , Tel Aviv University (Autor:in)
  • Yankel Gabet - , Tel Aviv University (Autor:in)
  • Lorenz C Hofbauer - , Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Ben Wielockx - , Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)

Abstract

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 RANKL/OPG 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 RANKL/OPG axis. Thus, osteogenic Epo/EpoR signaling controls bone mass maintenance and contributes to Epo-induced bone loss.

Details

OriginalspracheEnglisch
Seiten (von - bis)42
FachzeitschriftBone research
Jahrgang9
Ausgabenummer1
PublikationsstatusVeröffentlicht - 13 Sept. 2021
Peer-Review-StatusJa
Extern publiziertJa

Externe IDs

PubMedCentral PMC8437981
Scopus 85114900476
ORCID /0000-0002-8691-8423/work/142236018

Schlagworte