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Cardiovascular Research Advance Access originally published online on November 17, 2008
Cardiovascular Research 2009 81(2):278-285; 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

Leucocyte cathepsin K affects atherosclerotic lesion composition and bone mineral density in low-density lipoprotein receptor deficient mice

Jian Guo1, Ilze Bot1,*, Ramon de Nooijer1,2, Sandra J. Hoffman3, George B. Stroup3, Erik A.L. Biessen1, G. Martin Benson4, Pieter H.E. Groot4, Miranda Van Eck1 and Theo J.C. Van Berkel1

1 Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research (LACDR), Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands
2 Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
3 Department of Bone and Cartilage Biology, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA 19406, USA
4 Atherosclerosis Department, GlaxoSmithKline Pharmaceuticals, Stevenage, UK

* Corresponding author. Tel: +31 71 5276213; fax: +31 71 5276032.E-mail address: i.bot{at}lacdr.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 leucocyte CatK in atherosclerotic plaque remodelling.

Methods and results: To assess the biological role of leucocyte CatK, we used the technique of bone marrow transplantation to selectively disrupt CatK in the haematopoietic system. Total bone marrow progenitor cells from CatK+/+, CatK+/–, and CatK–/– mice were transplanted into X-ray irradiated low-density lipoprotein receptor knockout (LDLr–/–) mice. The selective silencing of leucocyte 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. The absence of leucocyte 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 in the apoptotic and necrotic area in plaques of mice transplanted with CatK–/– bone marrow.

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

KEYWORDS Bone marrow transplantation; Cathepsin K; Atherosclerosis; Bone remodelling; Atherosclerotic plaque composition

Time for primary review: 17 days


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