Emerging role of circulating calcifying cells in the bone-vascular axis.
Emerging role of circulating calcifying cells in the bone-vascular axis.
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DOI：
10.1161/circulationaha.112.090860
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发表时间：
2012-06-05
期刊：
影响因子：
37.8
通讯作者：
Khosla S
中科院分区：
文献类型：
--
作者：
Fadini GP;Rattazzi M;Matsumoto T;Asahara T;Khosla S
衰老与骨质疏松症和血管疾病的发展有关，越来越多的证据表明骨代谢和血管系统之间存在联系。1许多横断面和纵向研究已经证明骨矿物质密度和血管钙化之间存在反向的独立关联，2-5这似乎是动脉粥样硬化和相关心血管风险的预测因素。6此外，在前瞻性研究中，低骨矿物质密度与心血管事件风险增加相关。值得注意的是，高骨转换本身与老年受试者心血管死亡率增加相关，与年龄、性别、总体健康状况、血清甲状旁腺激素水平和髋部骨折状态无关。这就提出了一个有趣而重要的问题，即可能导致骨丢失、血管疾病和/或钙化的潜在机制。炎症和氧化应激是骨质疏松症和动脉粥样硬化的共同土壤，并可能解释这些疾病的巧合。8，9研究人员还在调查骨骼和血管疾病之间是否存在因果关系。这些研究主要关注骨保护素/核因子-κB受体激活剂（RANK）/RANK配体三联体、血浆胎球蛋白-A矿物质复合物/钙蛋白颗粒、成纤维细胞生长因子-23/Klotho轴和循环钙化细胞（表1）。在小鼠中，缺乏破骨细胞成熟的抑制剂骨保护素，随后发生骨质疏松症和血管钙化。10最初的发现表明，骨保护素/RANK/RANK配体三联体的失调在骨血管轴的病理生物学中起着核心作用。然而，尽管一系列研究表明骨保护素对血管细胞的直接生物学作用，但没有明确的证据表明骨保护素对动脉钙化的预防与骨吸收的作用无关。事实上，有几项研究报告称，抗吸收药物治疗的动物血管钙化减少，而抗动脉粥样硬化他汀类药物可能改善骨密度。12成纤维细胞生长因子-23是一种骨激素，可促进磷酸盐排泄并抑制肾脏中维生素D的生物合成。Klotho作为一种膜相关蛋白和分泌介质，负责成纤维细胞生长因子-23的肾脏特异性作用。在小鼠中，Klotho的缺失导致加速衰老，骨质减少和广泛的血管钙化。尽管Klotho和成纤维细胞生长因子-23缺失小鼠中观察到的大多数血管变化都与高磷酸盐血症有关，但还需要进行额外的研究来剖析成纤维细胞生长因子-23和Klotho在骨血管轴中的作用。
Aging is associated with the development of both osteo-porosis and vascular disease, and there is increasing evidence for a link between bone metabolism and the vasculature. 1 A number of cross-sectional and longitudinal studies have demonstrated inverse, independent associations between bone mineral density and vascular calcification, 2–5 which appear to be predictive of atherosclerosis and related cardiovascular risk. 6 In addition, low bone mineral density has been associated with increases in the risk of cardiovascular events in prospective studies. 3 Of interest, high bone turnover itself is associated with increased cardiovascular mortality in elderly subjects independently of age, sex, overall health, serum parathyroid hormone levels, and hip fracture status. 7 This raises the interesting and important question of possible underlying mechanisms that may be driving bone loss, vascular disease, and/or calcification. Inflammation and oxidative stress represent a common soil for osteoporosis and atherosclerosis and might explain the coincidence of these diseases. 8, 9 Researchers are also investigating the existence of a causal connection between bone and vascular diseases. These studies are focusing mainly on the osteoprotegerin/receptor activator of nuclear factor-κB (RANK)/RANK ligand triad, the plasma fetuin-A mineral complexes/calciprotein particles, fibroblast growth factor-23/Klotho axis, and circulating calcifying cells (Table 1). In mice, the lack of osteoprotegerin, an inhibitor of osteoclast maturation, is followed by the development of both osteoporosis and vascular calcification. 10 The original finding suggested a central role for dysregulation in the osteoprotegerin/RANK/RANK ligand triad in the pathobiology of the bone-vascular axis. However, despite a series of studies showing direct biological effects of osteoprotegerin on vascular cells, there is no definitive demonstration that prevention of arterial calcification by osteoprotegerin is independent of actions on bone resorption. Indeed, several studies report reduced vascular calcification in animals treated with antiresorptive drugs, 11 whereas the antiatherosclerotic statins may improve bone mineral density. 12Fibroblast growth factor-23 is a bone hormone that promotes phosphate excretion and inhibits vitamin D biosynthesis in the kidney. Klotho, which acts as both a membraneassociated protein and a secreted mediator, is responsible for the kidney-specific action of fibroblast growth factor-23. 13 In mice, deletion of Klotho leads to accelerated aging, with osteopenia and extensive vascular calcification. 14 Although hyperphosphatemia is implicated in most of the vascular changes observed in Klotho and fibroblast growth factor-23–null mice, 15 additional studies are needed to dissect the contribution of fibroblast growth factor-23 and Klotho in the bone-vascular axis.