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Cardiovascular Research Advance Access [Accepted Manuscript] published online on November 17, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn311
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.

Leukocyte cathepsin K affects atherosclerotic lesion composition and bone mineral density in LDL-receptor deficient mice

Jian Guo*, Ilze Bot*, Ramon de Nooijer*,#, Sandra J. Hoffman{ddagger}, George B. Stroup{ddagger}, Erik A.L. Biessen*, G. Martin Benson, Pieter H.E. Groot, Miranda Van Eck* and Theo J.C. Van Berkel*

* Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Leiden, The Netherlands
# Dept. of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
{ddagger} Department of Bone and Cartilage Biology, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA 19406, USA
Atherosclerosis Department, GlaxoSmithKline Pharmaceuticals, Stevenage, UK

Correspondence to: Theo J.C. Van Berkel, Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research (LACDR), Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands. Tel: +31-71-5276216; Fax: +31-71-5276032 Email: t.berkel{at}chem.leidenuniv.nl

Aims: Cathepsin K (CatK), an established drug target for osteoporosis, has been reported to be upregulated in atherosclerotic lesions. Due to its proteolytic activity CatK may influence the atherosclerotic lesion composition and stability. In this study, we investigated the potential role of leukocyte CatK in atherosclerotic plaque remodeling.

Methods: To assess the biological role of leukocyte CatK, we used the technique of bone marrow transplantation to selectively disrupt CatK in the hematopoietic system. Total bone marrow progenitor cells from CatK+/+, CatK+/– and CatK–/– mice were transplanted into X-ray irradiated LDL receptor knockout (LDLr–/–) mice.

Results: The selective silencing of leukocyte CatK resulted in phenotypic changes in bone formation with an increased total bone mineral density in the CatK–/– chimeras and an effect of gene dosage. Absence of leukocyte CatK resulted in dramatically decreased collagen and increased macrophage content of the atherosclerotic lesions while lesion size was not affected. The atherosclerotic lesions also demonstrated less elastic lamina fragmentation and a significant increase of the apoptotic and necrotic area in plaques of mice transplanted with CatK–/– bone marrow.

Conclusions: Leukocyte CatK is an important determinant of atherosclerotic plaque composition, vulnerability and bone remodeling, rendering CatK an attractive target for pharmaceutical modulation in atherosclerosis and osteoporosis.

KEYWORDS bone marrow transplantation; cathepsin K; atherosclerosis; bone remodeling; atherosclerotic plaque composition

Time for primary review: 17 Days


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