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临床上广泛存在的 类似于骨形成的显著过程。矛盾的是，它与 患有骨质疏松症。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和阻断基质 骨细胞在体外发生钙化。我们进一步表明，高脂血症是 与显著降低的骨密度和骨量有关 老鼠。体内骨密度不仅受成骨细胞的调节 不仅与破骨细胞的活性有关，还与破骨细胞的吸收活性有关。和影响 氧化脂质和高脂血症对破骨细胞分化的影响 功能是未知的。在骨质疏松症中，破骨细胞活动超过 成骨活性。我们现在假设氧化的脂类调节 骨吸收破骨细胞的分化和功能 和动脉壁。这些脂类对破骨细胞的调节作用 分化也可能取决于基质细胞产生的因子。 在两张纸巾里。 具体地说，我们假设(1)破骨细胞样细胞存在于 在动脉壁和骨骼中均受氧化脂质的调节 组织，(2)氧化脂质调节基质细胞的产生和 对破骨细胞因子如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预防这两种情况。 高脂血症诱导体内血管钙化和骨丢失。 为了检验这些特定的假设，我们将：1)检查人类和小鼠的动脉 破骨细胞标志物和活性的标本以及是否氧化的测试 利用血管和骨的体外模型研究脂类对破骨细胞生成的影响 组织，2)检测治疗前后基质细胞产生M-CSF、IL-6和RANKL 经氧化脂质处理后，检测基质细胞对 体外和体内的溶骨刺激、甲状旁腺激素和白介素6。和3)确定 对氧磷酶灭活氧化脂质是否阻断氧化脂质 和高脂血症诱导的血管钙化和骨丢失 在活体内。氧化脂质调节矿物质的机制研究进展 吸收将为骨质疏松症和血管疾病提供新的治疗方法 钙化，包括生物控制回归的可能性 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.