Deferoxamine inhibits iron-uptake stimulated osteoclast differentiation by suppressing electron transport chain and MAPKs signaling.
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.
['Zhang|Jian|J|', 'Hu|Wentao|W|', 'Ding|Chong|C|', 'Yao|Gang|G|', 'Zhao|Hai|H|', 'Wu|Shuguang|S|']
D000818:Animals D001862:Bone Resorption D027682:Cation Transport Proteins D002454:Cell Differentiation D002478:Cells, Cultured D003676:Deferoxamine D004305:Dose-Response Relationship, Drug D045222:Electron Transport Chain Complex Proteins D005293:Ferritins D007501:Iron D007502:Iron Chelating Agents D008297:Male D008810:Mice, Inbred C57BL D020928:Mitogen-Activated Protein Kinases D010010:Osteoclasts D010766:Phosphorylation D017382:Reactive Oxygen Species D011990:Receptors, Transferrin D015398:Signal Transduction
Deferoxamine Osteoclast differentiation Electron transport chain MAPKs Iron uptake