Common Mediators of Vascular Calcification and Bone Dis*

描述（由申请人提供）： 血管钙化是一个积极调节的过程， 尿毒症、糖尿病、主动脉瓣狭窄患者的发病率和死亡率增加 狭窄和生物人工心脏瓣膜。流行病学研究表明 血管钙化与骨质疏松症和心血管疾病， 这表明存在共同的调节机制， 钙化可能会增加心脏病的风险。在人体血管中 和瓣膜，均观察到弥漫性钙化和异位骨 在病理条件下。这些类型之间的关系 矿化不清楚。也不清楚血管中膜或内膜 钙化有助于动脉粥样硬化的形成和/或进展 病变我们假设血管中的矿物质沉积 介质包括骨桥蛋白（OPN）、骨保护素（OPG）和基质玻璃 蛋白质（MGP），也是关键控制骨骼的形成， 一旦矿物质在血管壁中形成， 启动细胞分化和炎症机制，1）导致 新内膜形成并因此增加对斑块形成的敏感性， 和2）模拟软骨内骨形成，这可能解释了 钙化血管病变中的异位骨。以便查明共同 机制！控制骨骼和血管钙化，并了解 血管钙化、软骨化生和 动脉病变的发展，提出了三个目标。目标我将决定 中膜血管钙化、新生内膜形成和 MGP X OPN突变小鼠中的软骨化生。目标2将决定 在MGP X OPN小鼠中发现的骨和牙齿缺陷的机制。目标3将 确定高脂血症对软骨化生、血管 钙化和骨质疏松症。

DESCRIPTION (provided by applicant): Vascular calcification is an actively regulated process contributing to increased morbidity and mortality in, patients with uremia, diabetes, aortic stenosis and bioprosthetic heart valves. Epidemiological studies have linked vascular calcification with osteoporosis and cardiovascular disease, suggesting that common regulatory mechanisms exist, and that ectopic calcification may increase the risk of heart disease. In human blood vessels and valves, both diffuse calcification and ectopic bone have been observed under pathological conditions. The relationship between these types of mineralization is unclear. It is also unknown if media or intimal vascular calcification contributes to formation and/or progression of atherosclerotic lesions. We hypothesize that mineral deposition in blood vessels involves mediators including osteopontin (OPN), osteoprotegerin (OPG) and matrix gla proteins (MGP), that also critically control formation of the skeleton, and that once mineral forms in the vessel wall, an adaptive response ensues and initiates cellular differentiation and inflammatory mechanisms that 1) lead to neointima formation and hence increased susceptibility to plaque formation, and 2) mimic endochondral bone formation that may explain the appearance of ectopic bones in calcified vascular lesions. In order to identify common mechanisms! controlling bone and vascular calcification, and to understand the relationship between vascular calcification, cartilaginous metaplasia, and arterial lesion development, three aims are proposed. Aim I will determine the mechanism of medial vascular calcification, neointimal formation, and cartilaginous metaplasia in MGP X OPN mutant mice. Aim 2 will determine the mechanism of bone and tooth defects found in MGP X OPN mice. Aim 3 will determine the effect of hyperlipidemia on cartilaginous metaplasia, vascular calcification and osteoporosis in a mouse model of atherosclerosis.