Molecular regulation of vascular calcification in atherosclerosis

 描述（由申请人提供）：血管平滑肌细胞（VSMC）的内膜巨噬细胞浸润和成骨分化在动脉粥样硬化的发病机制中起重要作用。然而，很少有人知道这两个主要的细胞类型之间的串扰在动脉粥样硬化病变。在过去的资助期间，我们已经确定了平滑肌细胞（SMC）表达的成骨转录因子Runx 2在调节血管平滑肌细胞（VSMC）成骨分化和动脉粥样硬化血管钙化中的明确作用。此外，我们已经确定了动脉粥样硬化病变中VSMC钙化和巨噬细胞浸润以及血管破骨细胞（vOC）形成之间的正相关性。虽然破骨细胞样细胞以前观察到动脉粥样硬化病变，vOC的形成和功能的机制是未知的。我们的研究已经确定了SMC表达的Runx2依赖性RANKL（破骨细胞生成的关键调节因子）表达在促进巨噬细胞浸润和vOC形成中的重要新作用。破骨细胞的已知功能是吸收骨矿物质，在钙化的动脉粥样硬化病变周围观察到破骨细胞蛋白酶，提示vOC可能具有吸收血管钙化的功能。特别是，抗再吸收双膦酸盐药物已被证明可以抑制血管钙化。抗再吸收药物对骨骼和 血管系统提示不同的内在信号和组织特异性微环境，其差异性地控制骨和脉管系统中的矿化。我们发现vOC和钙化之间存在内在偶联，这支持了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，支持破骨细胞的促成骨功能。因此，我们假设血管破骨细胞诱导成骨祖细胞的募集和钙化，从而促进动脉粥样硬化中的血管钙化。目的1：探讨血管破骨细胞在调节血管钙化中的作用。目的二是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强烈支持vOC在动脉粥样硬化中调节血管钙化的作用。凭借一支在血管，破骨细胞和干细胞生物学，新动物模型，尖端技术和创新方法方面具有专业知识的多学科团队，该提案将首次确定vOC在动脉粥样硬化血管钙化发病机制中的调节作用，并阐明范式转变机制。这些研究的新发现不仅可以提高我们对血管钙化基本机制的理解，而且可以为开发新型抗偶联药物以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.