A novel biological function of soluble biglycan: Induction of erythropoietin production and polycythemia.
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-2α (HIF-2α). While mechanisms of hypoxia-dependent stabilization of HIF-2α protein are well established, data regarding oxygen-independent regulation of HIF-2α are sparse. In this study, we generated a novel transgenic mouse model, in which biglycan was constitutively overexpressed and secreted by hepatocytes (BGNTg), 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 BGNTgmice showed elevated hemoglobin concentrations, hematocrit values and enhanced total iron binding capacity, revealing a clinical picture of polycythemia. In BGNTgmice 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-2α 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-2α protein stabilization and Epo production presumably in an oxygen-independent manner, ultimately giving rise to secondary polycythemia.
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe-Universität Frankfurt am Main, Frankfurt am Main, Germany.
Helena
H
Frey
German Center for Environmental Health, Institute of Experimental Genetics and the German Mouse Clinic, Helmholtz-Zentrum München, Neuherberg, Germany.
Kristin
K
Moreth
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe-Universität Frankfurt am Main, Frankfurt am Main, Germany.
Louise Tzung-Harn
LT
Hsieh
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe-Universität Frankfurt am Main, Frankfurt am Main, Germany.
Jinyang
J
Zeng-Brouwers
German Center for Environmental Health, Institute of Experimental Genetics and the German Mouse Clinic, Helmholtz-Zentrum München, Neuherberg, Germany.|Gene Center, Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-Universität München, Feodor-Lynen Strasse 25, 81377, Munich, Germany.
Birgit
B
Rathkolb
German Center for Environmental Health, Institute of Experimental Genetics and the German Mouse Clinic, Helmholtz-Zentrum München, Neuherberg, Germany.
Helmut
H
Fuchs
German Center for Environmental Health, Institute of Experimental Genetics and the German Mouse Clinic, Helmholtz-Zentrum München, Neuherberg, Germany.
Valérie
V
Gailus-Durner
Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, 19107, USA.
Renato V
RV
Iozzo
German Center for Environmental Health, Institute of Experimental Genetics and the German Mouse Clinic, Helmholtz-Zentrum München, Neuherberg, Germany.|Lehrstuhl für Experimentelle Genetik, Center of Life and Food Science, Weihenstephan Technische Universität München, Freising-Weihenstephan, Germany.|German Center for Diabetes Research, Neuherberg, Germany.
Martin Hrabě
MH
de Angelis
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe-Universität Frankfurt am Main, Frankfurt am Main, Germany. schaefer@med.uni-frankfurt.de.
Liliana
0000-0002-3318-3005
L
Schaefer
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D058578:Biglycan / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004906:Erythrocyte Count; D004912:Erythrocytes / Q000378:metabolism / Q000473:pathology; D004921:Erythropoietin / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D006400:Hematocrit; D006454:Hemoglobins / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011086:Polycythemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D058578:Biglycan; D004921:Erythropoietin; D006454:Hemoglobins; D012333:RNA, Messenger; D051195:Toll-Like Receptor 2; D000099162:Endothelial PAS Domain-Containing Protein 1; C493486:Tlr2 protein, mouse
Damage-associated molecular pattern; Erythrocyte; Extracellular matrix; Hypoxia-inducible factor; Proteoglycan; Toll-like receptor