中国组织工程研究

中国组织工程研究 ›› 2016, Vol. 20 ›› Issue (14): 2007-2014.doi: 10.3969/j.issn.2095-4344.2016.14.004

• 骨髓干细胞 bone marrow stem cells • 上一篇    下一篇

铁过载诱导产生活性氧导致人骨髓间充质干细胞成骨成脂分化失平衡

韩艳久，刘国辉，刘 勇   

  1. 华中科技大学附属协和医院骨科，湖北省武汉市  430030
  • 收稿日期:2016-03-01 出版日期:2016-04-01 发布日期:2016-04-01
  • 通讯作者: 刘国辉，博士生导师，教授，主任医师，华中科技大学同济医学院附属协和医院骨科，湖北省武汉市 430056
  • 作者简介:韩艳久，男，1983年生，湖北省汉川市人，汉族，华中科技大学在读博士，主治医师，主要从事骨与软组织缺损研究。
  • 基金资助:

    国家自然科学基金项目(30973045)

Iron overload inhibits osteogenesis and promotes adipogenesis in human bone marrow mesenchymal stem cells by producing reactive oxygen

Han Yan-jiu, Liu Guo-hui, Liu Yong   

  1. Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
  • Received:2016-03-01 Online:2016-04-01 Published:2016-04-01
  • Contact: Liu Guo-hui, Doctoral supervisor, Professor, Chief physician, Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
  • About author:Han Yan-jiu, Studying for doctorate, Attending physician, Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
  • Supported by:

    the National Natural Science Foundation of China, No. 30973045

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摘要：

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文题释义：
铁过载：是指各种病因导致的铁离子在人体内过多的积聚，当血液中的铁超过转铁蛋白结合能力时，就会产生血液中未被转铁蛋白结合的游离铁，游离铁继而沉积于组织中；游离铁通过催化氧化反应等多种机制导致重要脏器的结构损害和功能障碍，而这种铁离子过度沉积的现象被称作“铁过载”。
骨髓间充质干细胞向成骨与成脂细胞分化的平衡：骨髓间充质干细胞同时是成骨细胞和脂肪细胞的来源细胞，其成骨-成脂分化能力的平衡与骨改建的稳态平衡密切相关。骨髓间充质干细胞向成骨与成脂细胞分化的平衡维系着髓内骨组织与脂肪组织量的平衡。一旦骨髓间充质干细胞过多地向成脂细胞方向分化，则向成骨细胞分化的细胞数就相应减少，进而引起成骨缺陷。
 
背景：最新研究显示，铁过载作为一种新的病因参与到了老年骨质疏松症的发病过程。但是铁过载导致老年骨质疏松症发病的机制仍不明确。骨髓间充质干细胞成骨/成脂分化平衡的调节在正常人体骨量稳定维持过程中扮演重要的角色。骨髓间充质干细胞成骨/成脂分化失调能够导致老年骨质疏松症的发生。铁对骨髓间充质干细胞成骨/成脂分化的影响仍不清楚。因此，研究铁离子对骨髓间充质干细胞成骨/成脂分化的影响，可以进一步明确铁过载在老年骨质疏松症发病过程中的作用。
目的：探讨铁过载导致人骨髓间充质干细胞成骨成脂分化失衡的机制，明确其在骨质疏松症发病过程中所起的作用。
方法：采用密度梯度离心法分离培养人骨髓间充质干细胞，根据不同的处理实验分为，正常组：不加特殊处理，采用等量生理盐水进行干预；枸橼酸亚铁组：采用不同浓度(10，20，30 μmol/L)的枸橼酸亚铁培养人骨髓间充质干细胞；抗氧化剂干预枸橼酸亚铁组：采用枸橼酸亚铁(30 μmol/L)处理人骨髓间充质干细胞后，同时采用N-乙酰胺半胱氨酸(0.5 mmol/L)进行干预。
结果与结论：①铁过载对人骨髓间充质干细胞增殖没有明显的抑制作用；②铁过载可促进人骨髓间充质干细胞内活性氧的产生；③铁过载抑制人骨髓间充质干细胞内c-Maf、Runx2的表达，促进人骨髓间充质干细胞内过氧化物酶体增殖物激活受体γ的表达，抑制人骨髓间充质干细胞生成钙结节、促进人骨髓间充质干细胞内脂滴的生成；④抗氧化剂抑制活性氧后，能够上调c-Maf的表达以及部分逆转铁过载对人骨髓间充质干细胞成骨/成脂分化平衡的干扰效果；⑤结果提示，铁过载诱导产生活性氧通过抑制c-Maf的表达，从而导致人骨髓间充质干细胞成骨成脂分化失衡；抗氧化剂能部分逆转铁过载导致的抑制效应。
中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程 
ORCID: 0000-0002-3548-2498(刘国辉)

关键词: 干细胞, 骨髓干细胞, 铁过载, 人骨髓间充质干细胞, 成骨分化, 成脂分化, 活性氧, c-Maf, Runx2, 过氧化物酶体增殖物激活受体γ, 国家自然科学基金

Abstract:

BACKGROUND: Iron overload as a new etiological factor participate in the pathogenesis of senile osteoporosis, but its mechanism remains unclear. But the mechanism of iron overload cause senile osteoporosis pathogenesis remains unclear. Osteogenic/adipogenic differentiation homeostasis of bone marrow mesenchymal stem cells (BMSCs) plays an important role in the maintenance of normal human bone mass, and its imbalance can lead to senile osteoporosis. Iron effects on the osteogenic/adipogenic differentiation of BMSCs remain unclear. Therefore, we clarify the role of iron overload in the pathogenesis of senile osteoporosis by studying the effect of iron overload on BMSCs osteogenic/adipogenic differentiation.
OBJECTIVE: To explore the effect of iron overload on the osteogenesis and adipogenesis of human BMSCs (hBMSCs) in vitro and to explicit the role of iron overload in the pathogenesis of senile osteoporosis.
METHODS: hBMSCs were isolated by using density gradient centrifugation method. Isolated cells were treated with normal saline as normal control group, treated with 10, 20, 30 μmol/L ferrous citrate to mimic iron overload conditions, or treated with 30 μmol/L ferrous citrate followed by 0.5 mmol/L N-acetylcysteine as an antioxidant.
RESULTS AND CONCLUSION: Iron overload did not remarkably inhibit the proliferation of hBMSCs, but it could promote the generation of reactive oxygen in hBMSCs. After treatment with ferrous citrate, the expression of c-Maf and Runx2 decreased, and the expression of peroxisome proliferator-activated receptor γ increased; moreover, formation of calcium nodules decreased, but lipid droplets were produced. N-acetylcysteine could inhibit the production of reactive oxygen and increase the expression of c-Maf induced by iron overload. These findings indicate that iron overload inhibits osteogenesis and promotes adipogenesis in hBMSCs through the generation of reactive oxygen. Meanwhile, c-Maf plays an essential role in the iron-overload induced differetiation imbalance.
中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程 

Key words: Iron, Cell Differentiation, Tissue Engineering