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.
Highlights
Erythropoietin (Epo) is a kidney-produced hormone that effectively stimulates erythropoiesis
Conditional loss of Epo acts via its receptor (EpoR) in osteogenic cells increases bone mass and suppresses bone turnover in female but not male mice To investigate whether EpoR has direct roles in osteoblast differentiation and/or function and bone mass maintenance, we knocked out EpoR in osteoprogenitor cells from 5 weeks of age using Osx-cre
EpoR deficiency was confirmed at the mRNA level in osteoblast cultures but did not result in a change in body weight compared to was upregulated (WT) expression (Supplementary Fig. 1A, B)
Summary
Erythropoietin (Epo) is a kidney-produced hormone that effectively stimulates erythropoiesis. It is used clinically to stimulate erythropoiesis in anemia resulting from chronic kidney disease, myelodysplastic syndromes, or cancer.[1,2,3,4] Epo signals via its receptor EpoR.[5,6] Deletion of Epo or EpoR in mice leads to embryonic lethality due to severe anemia, underscoring the relevance of EpoEpoR signaling in red blood cell production. Accumulating evidence shows, that Epo exerts extraerythropoietic activities in a variety of tissues. Given the frequent use of Epo in patients who already have compromised bone health, understanding its impact on bone is of central importance
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