Institute of Laboratory Animal Sciences, Guizhou University of Traditional Chinese Medicine, Guiyang, China.
School of Radiation Medicine and Protection, Soochow University, Suzhou, China.
Toxicol Lett. 2019 Oct 1;313:50-59. doi: 10.1016/j.toxlet.2019.06.007. Epub 2019 Jun 22.
Iron overload causes osteoporosis by enhancing osteoclastic bone resorption. During differentiation, osteoclasts demand high energy and contain abundant mitochondria. In mitochondria, iron is used for the synthesis of Fe-S clusters to support mitochondria biogenesis and electron transport chain. Moreover, mitochondrial reactive oxygen species (ROS) play an important role in osteoclastogenesis. Activation of MAPKs (ERK1/2, JNK, and p38) by ROS is essential and contribute to osteoclast differentiation. How iron chelation impairs electron transport chain and ROS dependent MAPKs activation during osteoclast differentiation is unknown. This study aimed to determine the direct effects of iron chelation on osteoclast differentiation, electron transport chain and MAPKs activation. In the present study, we found that when iron chelator, deferoxamine (DFO), was added, a dose-dependent inhibition of osteoclast differentiation and bone resorption was observed. Supplementation of transferrin-bound iron recovered osteoclastogenesis. Iron chelation resulted in a marked decrease in ferritin level, and increased expression of transferrin receptor 1 and ferroportin. As an iron chelator, DFO negatively affected mitochondrial function through decreasing activities of all the complexes. Expressions of mitochondrial subunits encoded both by mitochondrial and nuclear DNA were decreased. DFO augmented production of mitochondrial ROS, but inhibited the phosphorylation of ERK1/2, JNK, and p38, even in the presence of hydrogen peroxide. These results suggest that iron chelation directly inhibits iron-uptake stimulated osteoclast differentiation and suppresses electron transport chain. Iron chelation negatively regulates MAPKs activation, and this negative regulation is independent on ROS stimulation.
铁过载通过增强破骨细胞的骨吸收导致骨质疏松。在分化过程中，破骨细胞需要大量能量，并且富含线粒体。在线粒体中，铁用于合成 Fe-S 簇以支持线粒体生物发生和电子传递链。此外，线粒体活性氧 (ROS) 在破骨细胞分化中发挥重要作用。ROS 激活 MAPKs（ERK1/2、JNK 和 p38）对于破骨细胞分化至关重要，并有助于破骨细胞分化。铁螯合如何在破骨细胞分化过程中损害电子传递链和 ROS 依赖性 MAPKs 激活尚不清楚。本研究旨在确定铁螯合对破骨细胞分化、电子传递链和 MAPKs 激活的直接影响。在本研究中，我们发现当添加铁螯合剂去铁胺 (DFO) 时，观察到破骨细胞分化和骨吸收呈剂量依赖性抑制。转铁蛋白结合铁的补充恢复了破骨细胞生成。铁螯合导致铁蛋白水平显着下降，转铁蛋白受体 1 和铁蛋白表达增加。作为铁螯合剂，DFO 通过降低所有复合物的活性显着影响线粒体功能。编码自线粒体和核 DNA 的线粒体亚基的表达均降低。DFO 增加了线粒体 ROS 的产生，但抑制了 ERK1/2、JNK 和 p38 的磷酸化，即使存在过氧化氢也是如此。这些结果表明，铁螯合直接抑制铁摄取刺激的破骨细胞分化并抑制电子传递链。铁螯合负调节 MAPKs 激活，这种负调节独立于 ROS 刺激。
