Guo Jian, Bot Ilze, de Nooijer Ramon, Hoffman Sandra J, Stroup George B, Biessen Erik A L, Benson G Martin, Groot Pieter H E, Van Eck Miranda, Van Berkel Theo J C
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research , Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333CC Leiden, The Netherlands.
Cardiovasc Res. 2009 Feb 1;81(2):278-85. doi: 10.1093/cvr/cvn311. Epub 2008 Nov 17.
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.
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.
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.
组织蛋白酶K（CatK）是一种已确定的骨质疏松症药物靶点，据报道在动脉粥样硬化病变中上调。由于其蛋白水解活性，CatK可能影响动脉粥样硬化病变的组成和稳定性。在本研究中，我们调查了白细胞CatK在动脉粥样硬化斑块重塑中的潜在作用。
为了评估白细胞CatK的生物学作用，我们使用骨髓移植技术选择性地破坏造血系统中的CatK。将来自CatK（+/+）、CatK（+/-）和CatK（-/-）小鼠的全骨髓祖细胞移植到经X射线照射的低密度脂蛋白受体敲除（LDLr（-/-））小鼠体内。白细胞CatK的选择性沉默导致骨形成的表型变化，CatK（-/-）嵌合体的总骨矿物质密度增加以及基因剂量效应。白细胞CatK的缺失导致动脉粥样硬化病变的胶原蛋白显著减少，巨噬细胞含量增加，而病变大小不受影响。动脉粥样硬化病变还表现出弹性 lamina 碎片化减少，并且在移植了CatK（-/-）骨髓的小鼠斑块中凋亡和坏死区域显著增加。
白细胞CatK是动脉粥样硬化斑块组成、易损性和骨重塑的重要决定因素，使CatK成为动脉粥样硬化和骨质疏松症药物调节的有吸引力的靶点。
