Vitamin D reduces the expression of collagen and key profibrotic factors by inducing an antifibrotic phenotype in mesenchymal multipotent cells.
Vitamin D reduces the expression of collagen and key profibrotic factors by inducing an antifibrotic phenotype in mesenchymal multipotent cells.
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DOI：
10.1677/joe-08-0241
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发表时间：
2009-02
期刊：
影响因子：
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通讯作者：
Norris KC
中科院分区：
文献类型：
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作者：
Artaza JN;Norris KC
维生素D缺乏症是一个重要的公共卫生问题。血清 25-羟基维生素 D (25-OHD) 现在被认为是心血管和相关疾病 (CVD) 以及其他慢性疾病的独立预测因子。然而，人们对介导这些效应的生物学途径仍知之甚少。我们假设，将间充质多能细胞 (MMC) 暴露于维生素 D 的活性形式会增加选定的抗纤维化因子的表达，从而改善慢性疾病的进展。 MMCs 用 5'-氮杂胞苷引发以诱导纤维化表型，然后用活性维生素 D (1,25D) 或乙醇 <0·1% 作为媒介物以时间过程方式（30 分钟、1、5 和 24 小时，以及 4 和 7 天）进行处理。在 MMC 中添加 1,25D 可促进： a) 维生素 D 受体的表达和核易位增加； b) TGFB1 和纤溶酶原激活剂抑制剂 (SERPINE1) 的表达降低，这两种因子是众所周知的促纤维化因子； c) I型胶原蛋白、III型胶原蛋白和其他胶原蛋白亚型的表达减少； d) 几种抗纤维化因子的表达增加，例如 BMP7（一种 TGFB1 拮抗剂）、MMP8（一种胶原蛋白分解诱导剂）和卵泡抑素（一种促纤维化因子肌生长抑制素的抑制剂）。总之，向分化的 MMC 中添加 1,25D 显示了促纤维化信号通路和基因表达的减少，从而导致胶原蛋白沉积的减少。这项研究强调了维生素 D 减少纤维化的关键机制途径，并为测试维生素 D 补充剂作为 CVD 和相关纤维化疾病的预防和/或早期治疗策略的研究提供了理论依据。
Hypovitaminosis D is an important public health problem. Serum 25-hydroxyvitamin D (25-OHD) is now recognized as an independent predictor for cardiovascular and related diseases (CVD) as well as other chronic medical conditions. However, the biologic pathways through which these effects are mediated remain poorly understood. We hypothesized that exposing mesenchymal multipotent cells (MMCs) to the active form of vitamin D would increase the expression of selected antifibrotic factors that in turn would ameliorate the progression of chronic diseases. MMCs were primed with 5′-azacytidine to induce a fibrotic phenotype and then treated with active vitamin D (1,25D) or ethanol <0·1% as vehicle in a time course manner (30 min, 1, 5, and 24 h, and for 4 and 7 days). The addition of 1,25D to MMCs promotes: a) increased expression and nuclear translocation of the vitamin D receptor; b) decreased expression of TGFB1 and plasminogen activator inhibitor (SERPINE1), two well-known profibrotic factors; c) decreased expression of collagen I, III and other collagens isoforms; and d) increased expression of several antifibrotic factors such as BMP7 a TGFB1 antagonist, MMP8 a collagen breakdown inducer and follistatin, an inhibitor of the profibrotic factor myostatin. In conclusion, the addition of 1,25D to differentiated MMCs displays a decreased profibrotic signaling pathway and gene expression, leading to decrease in collagen deposition. This study highlights key mechanistic pathways through which vitamin D decreases fibrosis, and provides a rationale for studies to test vitamin D supplementation as a preventive and/or early treatment strategy for CVD and related fibrotic disorders.