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.

高促红细胞生成素 (Epo) 水平对成年生物的骨骼健康有害。接受高剂量 Epo 的成年小鼠由于骨形成受到抑制和骨吸收增加而失去骨量。在人类中，高血清 Epo 水平与老年男性的骨折有关。我们早期的研究表明 Epo 调节成骨细胞活性；然而，Epo 通过其受体 (EpoR) 在体内作用于成骨细胞的直接证据仍然缺失。在这里，我们创造了骨祖细胞中缺乏 EpoR 的小鼠，以专门解决这一差距。骨祖细胞中 EpoR 的缺失 ( EpoR:Osx-cre, cKO) 从 5 周龄开始并没有改变红细胞参数，但使 12 周龄雌性小鼠的椎骨体积增加了 25%。这与低骨转换有关。组织学（成骨细胞数量、骨形成率）和血清（P1NP、骨钙素）骨形成参数均降低，破骨细胞数量和 TRAP 血清水平也降低。从 cKO 与对照小鼠分离的成骨细胞前体的分化导致成骨细胞标记基因（包括 Runx2、Alp 和 Col1a1）在第 21 天的表达较低，而矿化能力相似。此外，决定成骨细胞支持破骨细胞潜力的 RANKL/OPG 比值显着降低了 50%。相似地，与对照成骨细胞或 cKO 破骨细胞前体共培养 cKO 成骨细胞产生的破骨细胞明显少于与对照成骨细胞共培养。最后，将雌性小鼠暴露于 Epo 泵（10 U·d^-1 ) 4 周仅在对照小鼠中导致小梁骨丢失 (-25%) 和破骨细胞数量增加（1.7 倍），在 cKO 小鼠中没有。我们的数据显示，骨祖细胞中的 EpoR 在通过 RANKL/OPG 轴调节成骨细胞功能和成骨细胞介导的破骨细胞生成方面至关重要。因此，成骨 Epo/EpoR 信号控制骨量维持并导致 Epo 诱导的骨丢失。