The regulation of iron metabolism by hepcidin contributes to unloading-induced bone loss.
Iron overload inhibits osteoblast function and promotes osteoclastogenesis. Hepcidin plays an important role in this process. The changes in iron content and the regulation of hepcidin under unloading-induced bone loss remain unknown. A hindlimb suspension model was adopted to simulate unloading-induced bone loss in mice. The results showed that iron deposition in both liver and bone was markedly increased in hindlimb unloaded mice, and was accompanied by the upregulation of osteoclast activity and downregulation of osteoblast activity. The iron chelator deferoxamine mesylate (DFO) reduced the iron content in bone and alleviated unloading-induced bone loss. The increased iron content in bone was mainly a result of the upregulation of transferrin receptor 1 (TfR1) and divalent metal transporter 1 with iron response element (DMT1+IRE), rather than changes in the iron transporter ferroportin 1 (FPN1). The hepcidin level in the liver was significantly higher, while the FPN1 level in the duodenum was substantially reduced. However, there were no changes in the FPN1 level in bone tissue. During hindlimb unloading, downregulation of hepcidin by siRNA increased iron uptake in bone and liver, which aggravated unloading-induced bone loss. In summary, these data show that unloading-induced bone loss was orchestrated by iron overload and coupled with the regulation of hepcidin by the liver.
Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, Shijiazhuang 050024, China; State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China.
Zi
Z
Xu
Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, Shijiazhuang 050024, China; State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China.
Weijia
W
Sun
State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China.
Yuheng
Y
Li
State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China.
Shukuan
S
Ling
Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, Shijiazhuang 050024, China; State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China.
Chenyang
C
Zhao
State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China.
Guohui
G
Zhong
State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China.
Dingsheng
D
Zhao
State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China.
Jinping
J
Song
Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, Shijiazhuang 050024, China.
Hailin
H
Song
State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China.
Jinqiao
J
Li
Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, Shijiazhuang 050024, China.
Linhao
L
You
Key Laboratory of Chinese Academy of Sciences for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China, Beijing 100190, China.
Guangjun
G
Nie
Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, Shijiazhuang 050024, China. Electronic address: chang7676@163.com.
Yanzhong
Y
Chang
State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China. Electronic address: yingxianli@aliyun.com.
Yingxian
Y
Li
D065567:Absorption, Physiological / Q000187:drug effects; D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D001842:Bone and Bones / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D064451:Hepcidins / Q000378:metabolism*; D019417:Hindlimb Suspension / Q000009:adverse effects*; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology / Q000627:therapeutic use; D019190:Iron Overload / Q000150:complications / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D034741:RNA, Small Interfering / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D064451:Hepcidins; D007502:Iron Chelating Agents; D034741:RNA, Small Interfering; D007501:Iron; D003676:Deferoxamine
Bone loss; Hepcidin; Iron; Osteoblast; Osteoclast