Erythropoietin directly stimulates osteoclast precursors and induces bone loss

Sahar Hiram-Bab, Tamar Liron, Naamit Deshet-Unger, Moshe Mittelman, Max Gassmann, Martina Rauner, Kristin Franke, Ben Wielockx, Drorit Neumann*, Yankel Gabet

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Erythropoietin (EPO) primarily regulates red blood cell formation, and EPO serum levels are increased on hypoxic stress (e.g., anemia and altitude). In addition to anemia, recent discoveries suggest new therapeutic indications for EPO, unrelated to erythropoiesis. We investigated the skeletal role of EPO using several models of overexpression (Tg6 mice) and EPO administration (intermittent/continuous, high/low doses) in adult C57Bl6 female mice. Using microcomputed tomography, histology, and serum markers, we found that EPO induced a 32%-61 % trabecular bone loss caused by increased bone resorption (+60%-88% osteoclast number) and reduced bone formation rate (219 to 274%; P< 0.05 throughout). EPO targeted the monocytic lineage by increasing the number of bone monocytes/macrophages, preosteoclasts, and mature osteoclasts. In contrast to the attenuated bone formation in vivo, EPO treatment in vitro did not inhibit osteoblast differentiation and activity, suggesting an indirect effect of EPO on osteoblasts. However, EPO had a direct effect on preosteoclasts by stimulating osteoclastogenesis in isolated cultures (+60%) via the Jak2 and PI3K pathways. In summary, our findings demonstrate that EPO negatively regulates bone mass and thus bears significant clinical implications for the potential management of patients with endogenously or therapeutically elevated EPO levels.

Original languageEnglish
Pages (from-to)1890-1900
Number of pages11
JournalFASEB Journal
Volume29
Issue number5
DOIs
StatePublished - 1 May 2015

Funding

FundersFunder number
Seventh Framework Programme282551
Schweizerischer Nationalfonds zur F&#x00F6;rderung der Wissenschaftlichen Forschung141053

    Keywords

    • Bone turnover
    • Macrophages
    • Osteoclastogenesis
    • Tg6 mice
    • Trabecular bone

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