Morony Sean, Tintut Yin, Zhang Zina, Cattley Russell C, Van Gwyneth, Dwyer Denise, Stolina Marina, Kostenuik Paul J, Demer Linda L
Department of Molecular Cellular and Integrative Physiology, University of California, Los Angeles, USA.
Circulation. 2008 Jan 22;117(3):411-20. doi: 10.1161/CIRCULATIONAHA.107.707380. Epub 2008 Jan 2.
The role of osteoprotegerin in vascular disease is unclear. Recent observational studies show that serum osteoprotegerin levels are associated with the severity and progression of coronary artery disease, atherosclerosis, and vascular calcification in patients. However, genetic and treatment studies in mice suggest that osteoprotegerin may protect against vascular calcification.
To test whether osteoprotegerin induces or prevents vascular disease, we treated atherogenic diet-fed ldlr(-/-) mice with recombinant osteoprotegerin (Fc-OPG) or vehicle for 5 months. Vehicle-treated mice developed significant, progressive atherosclerosis with increased plasma osteoprotegerin levels, consistent with observational studies, and approximately 15% of these atherosclerotic lesions developed calcified cartilage-like metaplasia. Treatment with Fc-OPG significantly reduced the calcified lesion area without affecting atherosclerotic lesion size or number, vascular cytokines, or plasma cholesterol levels. Treatment also significantly reduced tissue levels of aortic osteocalcin, a marker of mineralization.
These data support a role for osteoprotegerin in the vasculature as an inhibitor of calcification and a marker, rather than a mediator, of atherosclerosis.
骨保护素在血管疾病中的作用尚不清楚。近期的观察性研究表明，血清骨保护素水平与患者冠状动脉疾病、动脉粥样硬化和血管钙化的严重程度及进展相关。然而，小鼠的基因和治疗研究提示，骨保护素可能预防血管钙化。
为了测试骨保护素是诱导还是预防血管疾病，我们用重组骨保护素（Fc-OPG）或赋形剂处理喂食致动脉粥样化饮食的低密度脂蛋白受体基因敲除（ldlr(-/-)）小鼠5个月。与观察性研究一致，用赋形剂处理的小鼠出现了显著的、进行性的动脉粥样硬化，血浆骨保护素水平升高，并且这些动脉粥样硬化病变中约15%发生了钙化软骨样化生。用Fc-OPG治疗显著减少了钙化病变面积，而不影响动脉粥样硬化病变的大小或数量、血管细胞因子或血浆胆固醇水平。治疗还显著降低了主动脉骨钙素的组织水平，骨钙素是矿化的标志物。
这些数据支持骨保护素在脉管系统中作为钙化抑制剂以及动脉粥样硬化的标志物而非介质的作用。
