A novel biological function of soluble biglycan: Induction of erythropoietin production and polycythemia
A novel biological function of soluble biglycan: Induction of erythropoietin production and polycythemia
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DOI：
10.1007/s10719-016-9722-y
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发表时间：
2017-06-01
影响因子：
3
通讯作者：
Schaefer, Liliana
中科院分区：
文献类型：
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作者：
Frey, Helena;Moreth, Kristin;Schaefer, Liliana
继发性红细胞增多症是一种以循环成熟红细胞选择性增加为特征的疾病，是由缺氧诱导因子 2 α (HIF-2 α) 引发的促红细胞生成素 (Epo) 浓度升高引起的。虽然 HIF-2 α 蛋白的缺氧依赖性稳定机制已得到充分确立，但有关 HIF-2 α 的氧独立调节的数据却很少。在这项研究中，我们建立了一种新型转基因小鼠模型，其中双糖链蛋白聚糖由肝细胞（BGN（Tg））组成性过度表达和分泌，从而提供了释放到血流中的双糖链蛋白聚糖的恒定来源。我们发现，尽管小鼠表面上很正常，但它们的成熟循环红细胞有所增加。除了红细胞增多症外，BGN (Tg) 小鼠还表现出血红蛋白浓度、血细胞比容值升高和总铁结合能力增强，揭示了红细胞增多症的临床表现。在 BGN (Tg) 小鼠中，在肝脏和肾脏中观察到 Epo mRNA 表达显着增强，而在肝脏、肾脏和血液中发现 Epo 蛋白水平升高。从机制上讲，我们发现转基因动物的肝脏和肾脏中含有丰富的 HIF-2 α 蛋白。最后，通过在缺乏各种 Toll 样受体 (TLR) 的小鼠中短暂过度表达循环双糖链蛋白聚糖，我们确定双糖链蛋白聚糖促进 Epo 合成的这种新功能是通过与 TLR2 的选择性相互作用特异性介导的。因此，我们发现了一种可溶性双糖链蛋白聚糖的新生物途径，其可能以不依赖氧的方式诱导 HIF-2 α 蛋白稳定和 Epo 产生，最终导致继发性红细胞增多症。
Secondary polycythemia, a disease characterized by a selective increase in circulating mature erythrocytes, is caused by enhanced erythropoietin (Epo) concentrations triggered by hypoxia-inducible factor-2 alpha (HIF-2 alpha). While mechanisms of hypoxia-dependent stabilization of HIF-2 alpha protein are well established, data regarding oxygen-independent regulation of HIF-2 alpha are sparse. In this study, we generated a novel transgenic mouse model, in which biglycan was constitutively overexpressed and secreted by hepatocytes (BGN (Tg)), thereby providing a constant source of biglycan released into the blood stream. We discovered that although the mice were apparently normal, they harbored an increase in mature circulating erythrocytes. In addition to erythrocytosis, the BGN (Tg) mice showed elevated hemoglobin concentrations, hematocrit values and enhanced total iron binding capacity, revealing a clinical picture of polycythemia. In BGN (Tg) mice markedly enhanced Epo mRNA expression was observed in the liver and kidney, while elevated Epo protein levels were found in liver, kidney and blood. Mechanistically, we showed that the transgenic animals had an abundance of HIF-2 alpha protein in the liver and kidney. Finally, by transiently overexpressing circulating biglycan in mice deficient in various Toll-like receptors (TLRs), we determined that this novel function of biglycan to promote Epo synthesis was specifically mediated by a selective interaction with TLR2. Thus, we discovered a novel biological pathway of soluble biglycan inducing HIF-2 alpha protein stabilization and Epo production presumably in an oxygen-independent manner, ultimately giving rise to secondary polycythemia.