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Erythropoietin directly stimulates osteoclast precursors and induces bone loss


Hiram-Bab, Sahar; Liron, Tamar; Deshet-Unger, Naamit; Mittelman, Moshe; Gassmann, Max; Rauner, Martina; Franke, Kristin; Wielockx, Ben; Neumann, Drorit; Gabet, Yankel (2015). Erythropoietin directly stimulates osteoclast precursors and induces bone loss. FASEB Journal, 29(5):1890-1900.

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 (-19 to -74%; 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.-Hiram-Bab, S., Liron, T., Deshet-Unger, N., Mittelman, M., Gassmann, M., Rauner, M., Franke, K., Wielockx, B., Neumann, D., Gabet, Y. Erythropoietin directly stimulates osteoclast precursors and induces bone loss.

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 (-19 to -74%; 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.-Hiram-Bab, S., Liron, T., Deshet-Unger, N., Mittelman, M., Gassmann, M., Rauner, M., Franke, K., Wielockx, B., Neumann, D., Gabet, Y. Erythropoietin directly stimulates osteoclast precursors and induces bone loss.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
05 Vetsuisse Faculty > Institute of Veterinary Physiology
Dewey Decimal Classification:570 Life sciences; biology
Date:28 January 2015
Deposited On:15 Apr 2015 15:19
Last Modified:08 Dec 2017 12:48
Publisher:Federation of American Society of Experimental Biology
ISSN:0892-6638
Publisher DOI:https://doi.org/10.1096/fj.14-259085
PubMed ID:25630969

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