Cellular /Molecular Mechanisms of Vascular Calcification

该项目的重点是了解血管钙化和骨质疏松症的分子机制。当发现基质GLA蛋白（MGP）基因敲除小鼠具有广泛的血管钙化时，MGP强烈地参与了血管钙化的发病机制。基于该小鼠模型，MGP可能被认为是血管钙化的抑制因子。然而，在具有正常MGP基因的小鼠的钙化病变和人类病变中，MGP表达与病变钙化程度正相关。在目前的赠款期间，我们证明，MGP调节 骨形态发生蛋白（BMP-2），在下一个资助期间，我们将确定MGP在动脉壁中的调节作用及其与BMP-2相互作用的分子基础。本项目在当前资助期内的其他工作提供了重要的线索，解释了为什么许多进行性血管钙化的患者也有进行性骨质疏松症。氧化脂质被证明可以促进钙化血管细胞（CVC）的钙化，但抑制骨髓基质细胞的成骨细胞分化和矿化，骨髓基质细胞是成熟骨成骨细胞的前体。无论氧化脂质 在体外添加或通过给动脉粥样硬化易感的C57 BL/6 J（BL 6）小鼠喂食致动脉粥样硬化饮食来产生。这些氧化脂质也显示出促进破骨细胞生成和破骨细胞活化。在体内，给动脉粥样硬化易感的BL 6小鼠喂食致动脉粥样硬化饮食，导致骨矿物质密度和骨矿物质含量显著降低。给抗动脉粥样硬化的C3 H/HeJ小鼠喂食致动脉粥样硬化饮食会导致与BL 6小鼠相同程度的高脂血症，但C3 H/HeJ小鼠的骨矿物质密度或骨矿物质含量均未显著降低。在下一个资助期，我们建议确定这些观察的分子机制，我们将确定高密度脂蛋白（HDL），HDL的组分和HDL的模拟物是否会防止动脉粥样硬化小鼠模型中的骨丢失。这些研究可能会发现血管钙化和骨质疏松症的潜在新的治疗靶点。

This Project is focused on understanding the molecular mechanisms involved in vascular calcification and osteoporosis. Matrix GLA protein (MGP) was strongly implicated in the pathogenesis of vascular calcification when an MGP knockout mouse was found to have extensive vascular calcification. Based on this mouse model, MGP might be thought to be an inhibitory factor in vascular calcification. However, in calcified lesions of mice that have a normal MGP gene and in human lesions, MGP expression is postively correlated with the degree of lesion calcification. During the current grant period we demonstrated that MGP regulates bone morphogenetic protein (BMP-2), During the next grant period we will determine the molecular basis for the regulatory role of MGP in the artery wall and its interaction with BMP-2. Other work from this Project during the current grant period provided important clues as to why many patients with progressive vascular calcification also have progressive osteoporosis. Oxidized lipids were shown to promote calcification of calcifying vascular cells (CVC) but inhibited the osteoblastic differentiation and mineralization of marrow stromal cells that are the precursors to mature bone osteoblasts. This was true whether the oxidized lipids were added in vitro or were produced by feeding atherosclerosis suceptible C57BL/6J (BL6) mice an atherogenic diet. These oxidized lipids were also shown to promote osteoclastogenesis and osteoclast activation in vitro. In vivo, feeding an atherogenic diet to atherosclerosis susceptible BL6 mice produced a dramatic reduction in bone mineral density and bone mineral content. Feeding an atherogenic diet to atherosclerosis resistant C3H/HeJ mice causes the same degree of hyperlipidemia as in BL6 mice, but there was no significant reduction in either bone mineral density or bone mineral content in the C3H/HeJ mice. In the next grant period we propose to determine the molecular mechanisms for these observations and we will determine if high density lipoproteins (HDL), components of HDL, and mimetics of HDL will protect against bone loss in mouse models of atherosclerosis. These studies may identify potential new therapeutic targets in vascular calcification and osteoporosis.