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Frey, H.* ; Moreth, K. ; Hsieh, L.T.* ; Zeng-Brouwers, J.* ; Rathkolb, B. ; Fuchs, H. ; Gailus-Durner, V. ; Iozzo, R.V.* ; Hrabě de Angelis, M. ; Schaefer, L.*

A novel biological function of soluble biglycan: Induction of erythropoietin production and polycythemia.

Glycoconj. J. 34, 393–404 (2016)
Postprint DOI PMC
Open Access Green
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 (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-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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Damage-associated Molecular Pattern ; Erythrocyte ; Extracellular Matrix ; Hypoxia-inducible Factor ; Proteoglycan ; Toll-like Receptor; Toll-like; Hypoxia; Erythrocytosis; Proteoglycans; Expression; Mice; Hif-1-alpha; Decorin; Protein; Hif-1
Language english
Publication Year 2016
HGF-reported in Year 2016
ISSN (print) / ISBN 0282-0080
e-ISSN 1573-4986
Journal Glycoconjugate Journal
Quellenangaben Volume: 34, Issue: 3, Pages: 393–404 Article Number: , Supplement: ,
Publisher Springer
Publishing Place Norwell, Mass.
Reviewing status Peer reviewed
Institute(s) Institute of Experimental Genetics (IEG)
POF-Topic(s) 30201 - Metabolic Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500600-001
G-500600-003
G-500692-001
DOI 10.1007/s10719-016-9722-y
WOS ID WOS:000403322800011
Scopus ID 84986309913
PubMed ID 27600268
Erfassungsdatum 2016-09-09
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