The regulation of iron metabolism by hepcidin contributes to unloading-induced bone loss

Xu, Zi; Sun, Weijia; Li, Yuheng; Ling, Shukuan; Zhao, Chenyang; Zhong, Guangming; Zhao, Di; Song, Jinping; Song, Hailin; Li, Jinqiao; You, Linhao; Nie, Guangjun; Chang, Yan‐Zhong; Li, Yingxian

doi:10.1016/j.bone.2016.09.023

Cited by 62 publications

(61 citation statements)

References 28 publications

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“…Although iron overload is necessary for bone development, excessive iron inhibits osteoblast formation and promotes osteoclast resorption, eventually leading to osteoporosis . Recently, a study showed that unloading reduced genetic expression in bone formation and promoted genetic expression in bone resorption, which may be due to a significant increase in bone iron, whereas this abnormal expression of genes was significantly reversed with intraperitoneal injection of DFO in mice . As a special environment in space, HyMF can significantly enhance the decrease of osteoblasts and the increase of osteoclasts caused by HLU.…”

Section: Discussionsupporting

confidence: 70%

“…Recently, a long‐term spaceflight showed that increased body iron stores were found in astronauts and were associated with decreased BMD . On the ground, mechanical unloading‐induced bone loss in mice was connected with iron overload . In rats, a decrease in the levels of circulating iron and an increase in iron content of the spleen was found after unloading for 14 days .…”

Section: Introductionmentioning

confidence: 68%

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Disorder of Iron Metabolism Inhibits the Recovery of Unloading-Induced Bone Loss in Hypomagnetic Field

Xue

Yang

Luo

et al. 2019

Journal of Bone and Mineral Research

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Exposure of humans and animals to microgravity in spaceflight results in various deleterious effects on bone health. In addition to microgravity, the hypomagnetic field (HyMF) is also an extreme environment in space, such as on the Moon and Mars; magnetic intensity is far weaker than the geomagnetic field (GMF) on Earth. Recently, we showed that HyMF promoted additional bone loss in hindlimb unloading–induced bone loss, and the underlying mechanism probably involved an increase of body iron storage. Numerous studies have indicated that bone loss induced by mechanical unloading can be largely restored after skeletal reloading in GMF conditions. However, it is unknown whether this bone deficit can return to a healthy state under HyMF condition. Therefore, the purpose of this study is to examine the effects of HyMF on the recovery of microgravity‐induced bone loss, and illustrates the changes of body iron storage in this process. Our results showed that there was lower bone mineral content (BMC) in the HyMF reloading group compared to the GMF reloading group. Reloaded mice in the HyMF condition had a worse microstructure of femur than in the GMF condition. Femoral mechanical properties, including elastic modulus, stiffness, and ultimate stress, were poorer and toughness was higher in the HyMF group compared with the GMF group. Simultaneously, more iron content in serum, the tibia, liver, and spleen was found under HyMF reloading than GMF reloading. The iron chelator deferoxamine mesylate (DFO) decreased the iron content in the bone, liver, and spleen, and significantly relieved unloading‐induced bone loss under HyMF reloading. These results showed that HyMF inhibits the recovery of microgravity‐induced bone loss, probably by suppressing the elevated iron levels’ return to physiological level. © 2019 American Society for Bone and Mineral Research.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 68%

Disorder of Iron Metabolism Inhibits the Recovery of Unloading-Induced Bone Loss in Hypomagnetic Field

Xue

Yang

Luo

et al. 2019

Journal of Bone and Mineral Research

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“…Xu and coworkers reported that hepcidin, liver and bone iron all increase weightlessness in mice, through increasing osteoclast activity and decreasing osteogenic activity and bone mass. However, the loss of bone mass was more serious upon siRNA interference of hepcidin expression (Xu et al 2017). With respect to the mechanism, hepcidin promotes the differentiation and mineralization of osteoblasts through L-type Ca2+ channels and regulates osteoblasts through insulin receptor substrate 1, FPN, BMP6, bone morphogenetic protein 2, smad mothers against decapentaplegic and mitogen-activated protein kinase P38 signaling pathways to promote bone formation (Ma et al 2010, Xu et al 2011, Huading et al 2015, Liu et al 2018.…”

Section: Introductionmentioning

confidence: 99%

Hepcidin is an endogenous protective factor for osteoporosis by reducing iron levels

Zhang

Wang

et al. 2018

Journal of Molecular Endocrinology

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Postmenopausal osteoporosis is a global health issue. Although a lack of estrogen is considered the major reason for postmenopausal osteoporosis, other factors might also contribute the etiology of the disease. In previous reports, we and others proposed that iron accumulation after menopause accelerates osteoporosis, and here, we genetically modified the expression of an endogenous hormone, hepcidin, to modulate iron status in a mouse model. Our results show that hepcidin levels negatively correlate with bone loss in both knockout and overexpression (with ovariectomy) murine models. In addition, iron overload enhances reactive oxygen species (ROS) activity and attenuates the functions of primary osteoblasts, while iron depletion could reverse this phenomenon through inhibiting the functions of primary osteoclasts. Therefore, our results provide more evidence of the 'iron accumulation' hypothesis, which suggests that high iron levels are risk factors for osteoporosis, and the 'Huang's hypothesis' that hepcidin is a potential drug target for the prevention of postmenopausal osteoporosis.

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“…Ferroportin (FPN)-the only iron exporter protein known to exist in mammals, is a 62.5-kDa protein consisting of 12 transmembrane domains [10]. Studies [9] [11,12]have shown that mice lacking the hepcidin gene as well as humans with hepcidin gene mutations suffer severe iron overload or other related diseases. Ganz T et al [13] found that inactivation of the FPN gene was associated with severe iron overload in the liver and the pancreas.…”

Section: Introductionmentioning

confidence: 99%

Elevated hepcidin, ferroportin associated with glucose metabolism disorder in midpregnancy

Ma¹,

Cheng²,

Zhang³

et al. 2020

Preprint

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[Objective]: Hepcidin and ferroportin are major regulators of iron metabolism. Although many previous studies have shown that iron metabolism disorder may contribute to the pathogenesis of Type 2 diabetes mellitus (DM), few studies have investigated hepcidin and other iron metabolism parameters in women with gestational diabetes mellitus (GDM). The purpose of this study was to determine the relationship between hepcidin, ferroportin and GDM. [Methods]: A case-control study was conducted in 85 women with GDM and 85 women without GDM (controls) who received regular prenatal care at the Obstetrics and Gynecology Hospital of Fudan University from October 2015 to May 2016. Serum ferritin (SF), hepcidin (Hepc), ferroportin (FPN), and soluble transferrin receptor (sTfR), as well as other clinical parameters, were detected and analyzed in all groups. [Results]: The levels of fasting plasma glucose (FPG), oral glucose tolerance test (OGTT) 1-h and 2-h plasma glucose, glycated hemoglobin (HbA1c), SF, Hepc, FPN and sTfR as well as homeostasis model assessment for insulin resistance (HOMA-IR) were significantly higher in the GDM group (P<0.05 for all). In the GDM group, FPN was positively correlated OGTT-1 h and OGTT-2 h In the control group, only sTfR was positively correlated with OGTT-1 h. There was no correlation between the iron metabolism indicators in both GDM and control group.[Conclusion]: Hepc, FPN sRfR and SF levels were higher in the GDM group. Elevated Hepc and FPN are associated with glucose metabolism disorder and may play an important role in GDM.

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The regulation of iron metabolism by hepcidin contributes to unloading-induced bone loss

Cited by 62 publications

References 28 publications

Disorder of Iron Metabolism Inhibits the Recovery of Unloading-Induced Bone Loss in Hypomagnetic Field

Disorder of Iron Metabolism Inhibits the Recovery of Unloading-Induced Bone Loss in Hypomagnetic Field

Hepcidin is an endogenous protective factor for osteoporosis by reducing iron levels

Elevated hepcidin, ferroportin associated with glucose metabolism disorder in midpregnancy

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