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Thromb Haemost 2006; 95(04): 708-714
DOI: 10.1160/TH05-12-0800
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

Interleukin-4 differentially regulates osteoprotegerin expression and induces calcification in vascular smooth muscle cells

Lorenz C. Hofbauer
1   Department of Internal Medicine, Philipps-University, Marburg
,
Jörg Schrader
1   Department of Internal Medicine, Philipps-University, Marburg
,
Ute Niebergall
1   Department of Internal Medicine, Philipps-University, Marburg
,
Volker Viereck
2   Department of Obstetrics and Gynecology, Georg-August-University, Goettingen
,
Andreas Burchert
1   Department of Internal Medicine, Philipps-University, Marburg
,
Dieter Hörsch
1   Department of Internal Medicine, Philipps-University, Marburg
,
Klaus T. Preissner
3   Department of Biochemistry, Justus-Liebig-University, Giessen; Germany
,
Michael Schoppet
1   Department of Internal Medicine, Philipps-University, Marburg
› Author AffiliationsFinancial support: The study was supported by a Heisenberg fellowship from Deutsche Forschungsgemeinschaft (Ho 1875/3–1) to LCH and a grant from Deutsche Forschungsgemeinschaft (Ho 1875/5–2) to LCH and MS.
Further Information

Publication History

Received 14 December 2005

Accepted after revision 17 February 2006

Publication Date:
30 November 2017 (online)

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Summary

Vascular calcification is characterized by cellular transdifferentiation and expression of bone-related matrix proteins that result in the presence of bone-like structures in the vascular wall. Interleukin (IL)-4, a pleiotropic cytokine, and osteoprotegerin (OPG), an essential regulator of osteoclast biology, have both been linked to vascular disease. Here, we assessed the role of IL-4 and OPG in vascular calcification in vitro. IL-4 induced OPG mRNA levels and protein secretion by 5-fold in a dose-and time-dependent fashion in human coronary artery smooth muscle cells (CASMC). Activation of the transcription factor STAT6 preceded IL-4-induced OPG expression, and blockade of IL-4-induced STAT6 activation by the phospholipase C inhibitor D609 decreased OPG expression. Long-term exposure of IL-4 for 4 weeks resulted in transformation of CASMC towards an osteoblastic phenotype, based on the expression of the transcription factor Cbfa1 and increased mineral deposition. Notably, calcification of CASMC was inhibited by gene silencing of Cbfa1. During osteogenic transformation, IL-4 down-regulated OPG production in CASMC. IL-4 has differential effects in CASMC: While short-term exposure enhances OPG production through a STAT6-dependent mechanism, long-term exposure causes Cbfa1-dependent osteogenic transformation anda decreased production of OPG, an inhibitor of bone resorption.

Keywords

Cbfa1 - interleukin-4 - osteoprotegerin - smooth muscle cells - vascular calcification
 

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