Helmholtz Institute for Biomedical Engineering, Biointerface Group, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
Circ Res. 2012 Aug 17;111(5):575-84. doi: 10.1161/CIRCRESAHA.111.261479. Epub 2012 Jul 2.
Fetuin-A is a liver-derived plasma protein involved in the regulation of calcified matrix metabolism. Biochemical studies showed that fetuin-A is essential for the formation of protein-mineral complexes, called calciprotein particles (CPPs). CPPs must be cleared from circulation to prevent local deposition and pathological calcification.
We studied CPP clearance in mice and in cell culture to identify the tissues, cells, and receptors involved in the clearance.
In mice, fetuin-A-containing CPPs were rapidly cleared by the reticuloendothelial system, namely Kupffer cells of the liver and marginal zone macrophages of the spleen. Macrophages from scavenger receptor-AI/II (SR-A)-deficient mice cleared CPPs less efficiently than macrophages from wild-type mice, suggesting that SR-AI/II is involved in CPP binding and endocytosis. Accordingly, we found reduced clearance of CPPs in SR-A/MARCO-deficient mice.
We could demonstrate that fetuin-A-containing CPPs facilitate the clearance of mineral debris by macrophages via SR-A. Since the same receptor also contributes to the uptake of modified low-density lipoprotein particles in atherosclerosis, defective endocytosis of both types of particle may impinge on lipid as well as mineral debris clearance in calcifying atherosclerosis.
胎球蛋白-A 是一种肝脏衍生的血浆蛋白，参与调节钙化基质代谢。生化研究表明，胎球蛋白-A 对于蛋白-矿物质复合物的形成（称为钙磷蛋白颗粒，CPPs）是必需的。CPPs 必须从循环中清除，以防止局部沉积和病理性钙化。
我们在小鼠和细胞培养中研究 CPP 的清除，以确定参与清除的组织、细胞和受体。
在小鼠中，胎球蛋白-A 结合的 CPP 被网状内皮系统（即肝脏的枯否细胞和脾脏的边缘区巨噬细胞）迅速清除。来自清道夫受体-AI/II（SR-A）缺陷型小鼠的巨噬细胞清除 CPP 的效率低于来自野生型小鼠的巨噬细胞，表明 SR-AI/II 参与 CPP 的结合和内吞作用。因此，我们发现 CPP 在 SR-A/MARCO 缺陷型小鼠中的清除减少。
我们可以证明，含有胎球蛋白-A 的 CPP 通过 SR-A 促进巨噬细胞清除矿物质碎片。由于同一受体也有助于动脉粥样硬化中修饰的低密度脂蛋白颗粒的摄取，因此这两种颗粒的内吞作用缺陷可能会影响钙化动脉粥样硬化中的脂质和矿物质碎片的清除。
