Lipid Regulation of Vascular and Bone Osteoclastogenesis

描述（由申请人提供）： 血管钙化现在被认为是一种广泛的， 类似于骨形成的重要过程。巧合的是， 骨质疏松症两者都与动脉粥样硬化和高脂血症有关。我们 最近提供了氧化脂质调节矿化的证据， 血管细胞促进基质钙化， 体外骨细胞钙化。我们进一步表明，高脂血症是 与骨矿物质密度和含量显著降低相关， 小鼠体内骨密度不仅受成骨细胞的调节， 活性，但也通过破骨细胞的再吸收活性。和影响 氧化脂质和脂质过氧化对骨细胞分化的影响， 功能未知。在骨质疏松症中， 成骨细胞活性我们现在假设氧化脂质调节 骨中矿物质吸收骨细胞的分化和功能 和动脉壁。脂质对骨形成的调节作用 分化也可能依赖于基质细胞产生的因子 在两个组织中。 具体来说，我们假设（1）破骨细胞样细胞存在于 动脉壁以及骨中的氧化脂质，并受两者中的氧化脂质调节 组织，（2）氧化脂质调节基质细胞的生产， 对破骨细胞生成因子如M-CSF、RANKL、PTH和IL-6的反应，以及 (3)动脉粥样硬化保护酶对氧磷酶也能阻止 高血压诱导的血管钙化和骨丢失。 为了验证这些特定的假设，我们将：1）检查人类和小鼠的动脉 标本进行骨钙素标志物和活性检测，并检测是否氧化 使用血管和骨的体外模型研究脂质对破骨细胞生成的影响 组织，2）评估之前和之后基质细胞产生的M-CSF、IL-6和RANKL 用氧化脂质处理后，测试基质细胞对 溶骨刺激，PTH和IL-6在体外和体内。（3）确定 对氧磷酶对氧化脂质的失活是否阻断了氧化脂质 和高脂血症诱导的血管钙化和骨丢失， in vivo.阐明氧化脂质调节矿物质的机制 骨吸收将为骨质疏松症和血管疾病提供新的治疗方法。 钙化，包括生物学控制消退的可能性 血管钙化

DESCRIPTION (provided by applicant): Vascular calcification is now recognized as a widespread, clinically significant process similar to bone formation. Paradoxically, it correlates with osteoporosis. Both are linked to atherosclerosis and hyperlipidemia. We have recently provided evidence that oxidized lipids regulate mineralization, promoting matrix calcification by vascular cells and blocking matrix calcification by bone cells in vitro. We further showed that hyperlipidemia is associated with significantly reduced bone mineral density and content in mice. Bone mineral density in vivo is regulated not only by osteoblastic activity, but also by resorptive activity of osteoclasts. and effects of oxidized lipids and hyperlipidernia on osteoclastic differentiation and function are not known. In osteoporosis, osteoclastic activity overtakes osteoblastic activity. We now hypothesize that oxidized lipids regulate differentiation and function of mineral-resorbing osteoclastic cells in bone and artery wall. These regulatory effects of lipids on osteoclastic differentiation could also be dependent on factors produced by stromal cells in the two tissues. Specifically, we hypothesize (1) that osteoclast-like cells are present in artery wall as well as in bone and are regulated by oxidized lipids in both tissues, (2) that oxidized lipids regulate stromal cell production of and response to osteoclastogenic factors such as M-CSF, RANKL, PTH, and IL-6, and (3) that the atheroprotective enzyme paraoxonase also prevents both hyperlipidemia-induced vascular calcification and bone loss in vivo. To test these specific hypotheses we will: 1) examine human and mouse arterial specimens for osteoclastic markers and activity and test whether oxidized lipids affect osteoclastogenesis using in vitro models of vascular and bone tissue, 2) assess stromal cell production of M-CSF, IL-6 and RANKL before and after treatment with oxidized lipids and test stromal cell responsiveness to osteolytic stimuli, PTH and IL-6 in vitro and in vivo. and 3) determine whether deactivation of oxidized lipids by paraoxonase blocks oxidized lipid and hyperlipidemla- induced vascular calcification and bone loss in vitro and in vivo. Elucidating the mechanism by which oxidized lipids regulate mineral resorption will allow novel treatment approaches for osteoporosis and vascular calcification, including the possibility of biologically controlled regression of vascular calcification.