title: 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.
authors: *Department of Cell and Developmental Biology, Department of Anatomy and Anthropology, and Department of Medicine, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Institute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland; Department of Medicine III, Dresden University Medical Center, Dresden, Germany; and Institute of Pathology, University of Technology, Dresden, Germany.
authors: Sahar
authors: S
authors: Hiram-Bab
authors: *Department of Cell and Developmental Biology, Department of Anatomy and Anthropology, and Department of Medicine, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Institute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland; Department of Medicine III, Dresden University Medical Center, Dresden, Germany; and Institute of Pathology, University of Technology, Dresden, Germany.
authors: Tamar
authors: T
authors: Liron
authors: *Department of Cell and Developmental Biology, Department of Anatomy and Anthropology, and Department of Medicine, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Institute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland; Department of Medicine III, Dresden University Medical Center, Dresden, Germany; and Institute of Pathology, University of Technology, Dresden, Germany.
authors: Naamit
authors: N
authors: Deshet-Unger
authors: *Department of Cell and Developmental Biology, Department of Anatomy and Anthropology, and Department of Medicine, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Institute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland; Department of Medicine III, Dresden University Medical Center, Dresden, Germany; and Institute of Pathology, University of Technology, Dresden, Germany.
authors: Moshe
authors: M
authors: Mittelman
authors: *Department of Cell and Developmental Biology, Department of Anatomy and Anthropology, and Department of Medicine, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Institute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland; Department of Medicine III, Dresden University Medical Center, Dresden, Germany; and Institute of Pathology, University of Technology, Dresden, Germany.
authors: Max
authors: M
authors: Gassmann
authors: *Department of Cell and Developmental Biology, Department of Anatomy and Anthropology, and Department of Medicine, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Institute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland; Department of Medicine III, Dresden University Medical Center, Dresden, Germany; and Institute of Pathology, University of Technology, Dresden, Germany.
authors: Martina
authors: M
authors: Rauner
authors: *Department of Cell and Developmental Biology, Department of Anatomy and Anthropology, and Department of Medicine, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Institute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland; Department of Medicine III, Dresden University Medical Center, Dresden, Germany; and Institute of Pathology, University of Technology, Dresden, Germany.
authors: Kristin
authors: K
authors: Franke
authors: *Department of Cell and Developmental Biology, Department of Anatomy and Anthropology, and Department of Medicine, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Institute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland; Department of Medicine III, Dresden University Medical Center, Dresden, Germany; and Institute of Pathology, University of Technology, Dresden, Germany.
authors: Ben
authors: B
authors: Wielockx
authors: *Department of Cell and Developmental Biology, Department of Anatomy and Anthropology, and Department of Medicine, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Institute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland; Department of Medicine III, Dresden University Medical Center, Dresden, Germany; and Institute of Pathology, University of Technology, Dresden, Germany histo6@post.tau.ac.il yankel@post.tau.ac.il.
authors: Drorit
authors: D
authors: Neumann
authors: *Department of Cell and Developmental Biology, Department of Anatomy and Anthropology, and Department of Medicine, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Institute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland; Department of Medicine III, Dresden University Medical Center, Dresden, Germany; and Institute of Pathology, University of Technology, Dresden, Germany histo6@post.tau.ac.il yankel@post.tau.ac.il.
authors: Yankel
authors: Y
authors: Gabet
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001862:Bone Resorption / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004921:Erythropoietin / Q000502:physiology*; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D010012:Osteogenesis / Q000502:physiology; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055114:X-Ray Microtomography
chemical_list: C554270:EPO protein, human; D053245:RANK Ligand; D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; D004921:Erythropoietin
keywords: Tg6 mice; bone turnover; macrophages; osteoclastogenesis; trabecular bone