Iron deficiency accelerates intervertebral disc degeneration through affecting the stability of DNA polymerase epsilon complex.
Iron deficiency accelerates intervertebral disc degeneration through affecting the stability of DNA polymerase epsilon complex.
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缺铁通过影响DNA聚合酶ε复合物的稳定性加速椎间盘退变。
DOI：
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发表时间：
2018
影响因子：
2.2
通讯作者：
Zhang Fan
中科院分区：
文献类型：
--
作者：
Zhang Chunqiang;Wang Bing;Zhao Xueling;Li Xingguo;Lou Zhenkai;Chen Xun;Zhang Fan
铁作为含铁蛋白的重要辅因子，在维持DNA稳定性和细胞周期进程中发挥关键作用。铁稳态失调导致许多疾病的发病，如癌症和贫血。在这项研究中，我们发现缺铁和椎间盘退变（IDD）之间存在明显的相关性。通过基因芯片实验，我们发现大量基因在不同程度退变的组织中差异表达。其中，含铁基因，PolE，DNA聚合酶β的催化亚基（Pol ε），以及其他两个Pol ε亚基，包括PolE2和PolE3，显著下调，而一些参与凋亡的蛋白，如Caspase-3和-8，显著上调。通过补充铁螯合剂去铁胺（DFO）或敲除髓核（NP）细胞中的铁二价金属转运蛋白1（DMT 1）或转铁蛋白受体1（TfR1），我们发现PolE复合物成员的蛋白水平显著降低，而内在凋亡途径被激活。有趣的是，在用DMT 1或TfR敲低的NP细胞中，PolE的过表达不能逆转PolE复合物的稳定性和凋亡状态。综上所述，我们的研究表明，缺铁是IDD病情加重的一个重要因素。适当补充铁可能是缓解IDD患者症状的有效策略。
Iron serves as an important cofactor of iron-containing proteins that play critical roles in the maintenance of DNA stability and cell cycle progression. The disturbed iron homeostasis results in the pathogenesis of many diseases such as cancer and anemia. In this study, we found a clear correlation between iron deficiency and intervertebral disc degeneration (IDD). Through microarray experiments, we found that a large number of genes were differentially expressed in tissues with different degrees of degeneration. Among them, an iron-containing gene, PolE, the catalytic subunit of DNA polymerase epsilon (Polε), and the other two Polε subunits, including PolE2 and PolE3, were markedly downregulated, while some proteins involved in apoptosis such as Caspase-3 and -8 were significantly upregulated. By supplementation with an iron chelator deferoxamine (DFO) or knocking down either iron divalentmetal transporter 1 (DMT1) or transferrin receptor 1 (TfR1) in the nucleus pulposus (NP) cells, we found that the protein levels of PolE complex members were dramatically reduced, whereas the intrinsic apoptotic pathway was activated. Interestingly, overexpression of PolE in NP cells knocked down with either DMT1 or TfR could not reverse the stability of PolE complex and apoptosis status. In summary, our study suggests that iron deficiency is an important factor in the aggravation of IDD. Proper iron supplementation may be an effective strategy to alleviate the symptoms of patients with IDD.
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DOI：
10.1042/bj20101825
发表时间：
2011-03-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Wang J;Pantopoulos K
通讯作者：
Pantopoulos K
影响因子：
29
作者：
Shah YM;Matsubara T;Ito S;Yim SH;Gonzalez FJ
通讯作者：
Gonzalez FJ
影响因子：
29
作者：
Drakesmith H;Nemeth E;Ganz T
通讯作者：
Ganz T
影响因子：
--
作者：
Hiyama, Akihiko;Sakai, Daisuke;Risbud, Makarand V.;Tanaka, Masahiro;Arai, Fumiyuki;Abe, Koichiro;Mochida, Joji
通讯作者：
Mochida, Joji
影响因子：
4.1
作者：
Basu AK;Pande P;Bose A
通讯作者：
Bose A