Molecular regulation of vascular calcification in atherosclerosis

 描述(由申请人提供)：内膜巨噬细胞的渗透和血管平滑肌细胞(VSMC)的成骨分化在动脉粥样硬化的发病机制中起重要作用。然而，关于动脉粥样硬化病变中这两种主要细胞类型之间的相互作用，我们知之甚少。在过去的资助阶段，我们已经确定了SMC表达的成骨转录因子Runx2在调节动脉粥样硬化中VSMC的成骨分化和血管钙化中的确切作用。此外，我们还发现动脉粥样硬化病变中VSMC钙化与巨噬细胞的浸润和血管破骨细胞(VOC)的形成呈正相关。尽管以前在动脉粥样硬化病变中观察到破骨细胞样细胞，但VOC在动脉粥样硬化中的形成和作用机制尚不清楚。我们的研究发现，SMC表达的Runx2依赖的RANKL在促进巨噬细胞浸润和VOC形成方面具有重要的新作用。RANKL是破骨细胞形成的关键调节因子。已知的破骨细胞功能是吸收骨矿物质。钙化的动脉粥样硬化病变周围破骨细胞蛋白的观察表明，VOC可能在吸收血管钙化中起作用。矛盾的是，抗吸收双膦酸类药物已被证明能抑制血管钙化。抗吸收药物对骨骼和骨骼的相反作用 血管系统暗示不同的内在信号和组织特有的微环境，这些信号和微环境不同地控制着骨骼和血管系统中的矿化。我们发现VOC和钙化之间存在内在的偶联，这一发现支持VOC促进血管钙化的新范式。初步研究表明，破骨细胞促进祖细胞的迁移和成骨分化，支持破骨细胞的成骨功能。因此，我们假设血管破骨细胞诱导成骨前体细胞的募集和钙化，从而在动脉粥样硬化中促进血管钙化提出了两个目标。目的1确定血管破骨细胞在体内调节血管钙化的功能。目的2阐明血管破骨细胞调节血管钙化的机制。我们发表的结果和初步数据有力地支持了VOC在动脉粥样硬化中调节血管钙化的作用。随着一个多学科团队的建立，他们在血管、破骨细胞和干细胞生物学、新的动物模型、尖端技术和创新方法方面拥有成熟的专业知识，该提案将首次确定VOC在调节动脉粥样硬化中血管钙化的发病机制中的作用，并阐明范式转换机制。这些研究中获得的新见解不仅可以加深我们对血管钙化基本机制的理解，还可以为开发新型抗偶联药物预防和治疗动脉粥样硬化中的血管钙化提供指导。

 DESCRIPTION (provided by applicant): Intimal macrophage infiltration and osteogenic differentiation of vascular smooth muscle cells (VSMC) contribute significantly to the pathogenesis of atherosclerosis. However, little is known about the crosstalk between these two major cell types in atherosclerotic lesions. In the past funding period, we have identified a definitive role of smooth muscle cell (SMC)-expressed osteogenic transcription factor Runx2 in regulating osteogenic differentiation of VSMC and vascular calcification in atherosclerosis. Moreover, we have identified a positive correlation between VSMC calcification and macrophage infiltration and formation of vascular osteoclasts (vOC) in atherosclerotic lesions. Although osteoclast-like cells were observed previously in atherosclerotic lesions, the mechanisms of formation and function of vOC in atherosclerosis is unknown. Our studies have identified an important new role of SMC-expressed Runx2-dependent expression of RANKL, the key regulator for osteoclastogenesis, in promoting macrophage infiltration and vOC formation. The known function of osteoclasts is to resorb bone mineral. The observation of osteoclastic proteases around the calcified atherosclerotic lesions suggests that vOC may function to resorb vascular calcification. Paradoxically, the anti-resorption bisphosphonate drugs have been shown to inhibit vascular calcification. The opposite effects of anti-resorbing drugs on the skeletal and vascular systems suggest different intrinsic signals and tissue-specific microenvironments that differentially govern the mineralization in bone and in the vasculature. Our finding of an intrinsi coupling between vOC and calcification supports a novel paradigm that vOC promotes vascular calcification. Preliminary studies demonstrated that osteoclasts promoted migration and osteogenic differentiation of progenitor cells, supporting a pro-osteogenic function of osteoclasts. Therefore, we hypothesize that vascular osteoclasts induce recruitment and calcification of osteogenic progenitor cells that promote vascular calcification in atherosclerosis Two Aims are proposed. Aim 1 is to determine the function of vascular osteoclasts in regulating vascular calcification in vivo. Aim 2 is to elucidate the mechanisms of vascular osteoclasts in regulating vascular calcification. Our published results and preliminary data strongly support the role of vOC in regulating vascular calcification in atherosclerosis. With a multidisciplinary team with established expertise in vascular, osteoclast and stem cell biology, new animal models, cutting-edge technologies and innovative approaches, the proposal will determine for the first time the function of vOC in regulating pathogenesis of vascular calcification in atherosclerosis, and elucidate the paradigm-shifting mechanisms. The novel insights gained in these studies may not only improve our understanding of basic mechanisms of vascular calcification, but also provide guidance for developing novel anti-coupling drugs to prevent and treat vascular calcification in atherosclerosis.