Hiram-Bab Sahar, Liron Tamar, Deshet-Unger Naamit, Mittelman Moshe, Gassmann Max, Rauner Martina, Franke Kristin, Wielockx Ben, Neumann Drorit, Gabet Yankel
*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.
*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
FASEB J. 2015 May;29(5):1890-900. doi: 10.1096/fj.14-259085. Epub 2015 Jan 28.
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.
促红细胞生成素（EPO）主要调节红细胞生成，在缺氧应激（如贫血和高原环境）时血清EPO水平会升高。除贫血外，最近的发现提示了EPO与红细胞生成无关的新治疗适应症。我们使用几种过表达模型（Tg6小鼠）和在成年C57Bl6雌性小鼠中给予EPO（间歇性/持续性，高/低剂量）的方式，研究了EPO在骨骼方面的作用。通过微型计算机断层扫描、组织学和血清标志物检测，我们发现EPO导致小梁骨丢失32%-61%，这是由骨吸收增加（破骨细胞数量增加60%-88%）和骨形成率降低（-19%至-74%；各处P<0.05）所致。EPO通过增加骨单核细胞/巨噬细胞、破骨细胞前体细胞和成熟破骨细胞的数量，作用于单核细胞谱系。与体内骨形成减弱相反，体外EPO处理并未抑制成骨细胞的分化和活性，提示EPO对成骨细胞有间接作用。然而，EPO通过Jak2和PI3K途径在分离培养物中刺激破骨细胞生成（增加60%），对破骨细胞前体细胞有直接作用。总之，我们的研究结果表明EPO对骨量有负性调节作用，因此对于内源性或治疗性EPO水平升高的患者的潜在管理具有重要的临床意义。
