Vitamin E decreases bone mass by stimulating osteoclast fusion
Vitamin E decreases bone mass by stimulating osteoclast fusion
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DOI：
10.1038/nm.2659
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发表时间：
2012-04-01
期刊：
影响因子：
82.9
通讯作者：
Takeda, Shu
中科院分区：
文献类型：
--
作者：
Fujita, Koji;Iwasaki, Makiko;Takeda, Shu
骨稳态通过成骨细胞骨形成和成骨细胞骨吸收之间的平衡来维持（1-3）。破骨细胞是由单核前破骨细胞融合形成的多核细胞（1，2，4，5）。脂溶性维生素，如维生素D，是维持骨骼完整性的关键。然而，维生素E在骨重建中的作用尚不清楚。在这里，我们发现缺乏α-生育酚转移蛋白的小鼠（Ttpa（-/-）小鼠），一种遗传性维生素E缺乏症的小鼠模型（6），由于骨吸收减少而具有高骨量。基于细胞的分析表明，α-生育酚刺激破骨细胞融合，独立于其抗氧化能力，通过诱导树突细胞特异性跨膜蛋白的表达，破骨细胞融合的必需分子，通过激活促分裂原活化蛋白激酶14（p38）和小眼症相关转录因子，以及其直接募集至Tm 7sf 4（编码DC-STAMP的基因）启动子（7-9）。事实上，在Ttpa（-/-）小鼠中观察到的骨异常被Tm 7sf 4转基因挽救。此外，喂食α-生育酚补充饮食的野生型小鼠或大鼠，其含有与许多人消耗的补充剂相当量的α-生育酚，骨质丢失。这些结果表明，血清维生素E是通过其调节破骨细胞融合的骨量的决定因素。
Bone homeostasis is maintained by the balance between osteoblastic bone formation and osteoclastic bone resorption(1-3). Osteoclasts are multinucleated cells that are formed by mononuclear preosteoclast fusion(1,2,4,5). Fat-soluble vitamins such as vitamin D are pivotal in maintaining skeletal integrity. However, the role of vitamin E in bone remodeling is unknown. Here, we show that mice deficient in alpha-tocopherol transfer protein (Ttpa(-/-) mice), a mouse model of genetic vitamin E deficiency(6), have high bone mass as a result of a decrease in bone resorption. Cell-based assays indicated that alpha-tocopherol stimulated osteoclast fusion, independent of its antioxidant capacity, by inducing the expression of dendritic-cell-specific transmembrane protein, an essential molecule for osteoclast fusion, through activation of mitogen-activated protein kinase 14 (p38) and microphthalmia-associated transcription factor, as well as its direct recruitment to the Tm7sf4 (a gene encoding DC-STAMP) promoter(7-9). Indeed, the bone abnormality seen in Ttpa(-/-) mice was rescued by a Tm7sf4 transgene. Moreover, wild-type mice or rats fed an alpha-tocopherol-supplemented diet, which contains a comparable amount of alpha-tocopherol to supplements consumed by many people, lost bone mass. These results show that serum vitamin E is a determinant of bone mass through its regulation of osteoclast fusion.