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Irp2 Knockout Causes Osteoporosis by Inhibition of Bone Remodeling

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Abstract

It has been found that iron disorder may lead to osteoporosis. However, the mechanism has been little explored. In the present study, we try to investigate the effects of iron disorder on bone metabolism using Irp2 knockout (Irp2−/−) mice. Female Irp2−/− mice were used in this study. Bone mineral density (BMD) was measured by Micro-CT. Serum markers for bone turnover were measured by enzyme-linked immunosorbent assay. Content of iron was measured in bone and liver tissue, and Vitamin D 25-hydroxylase (CYP2R1) content was measured in liver tissue. Relative gene expression involved in iron export and uptake, and some genes involved in activities of osteoblast and osteoclast were all measured by real-time PCR and western blot. Compared to wild-type mice, Irp2−/− mice exhibited reduced BMD, bone iron deficiency, and hepatic iron overload. Serum levels of 25(OH)D3 and markers for bone formation such as bone alkaline phosphatase (Balp), bone-gla-protein (BGP), and type I collagen alpha1 chain (Col I α1) were decreased, while markers for bone resorption including cathepsin K (Ctsk) and tartrate-resistant acid phosphatase (Trap) were all significantly increased. Hepatic CYP2R1 level was decreased in Irp2−/− mice compared with wild-type control mice. Compared to wild-type C57BL6 control mice, the expression of genes involved in osteoblast activity such as Balp, BGP, and Col I α1 were all significantly decreased in bone tissue, while genes for osteoclast activity such as Ctsk and Trap were all markedly increased in Irp2−/− mice at mRNA level. Genes involved in iron storage, uptake, and exporting were also measured in bone tissue. Posttranscriptionally decreased ferritin (FTL), ferroportin 1 (FPN1), and increased transferrin receptor 1 (TfR1) gene expressions have been unexpectedly found in bone tissue of Irp2−/− mice. Irp2−/− mice exhibit reduced bone iron content and osteoporosis. Decreased circulating 25(OH)D3 levels promoted activity of osteoclast, while impaired activity of osteoblast may contribute to pathogenesis of osteoporosis. And, reduced bone iron content may not be totally caused by TfR1-dependent pathways.

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Acknowledgements

We acknowledge the Beijing Synchrotron Radiation Facility for the beam time. This work was supported by the National Natural Science Foundation of China (Grant Number 31471035).

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  1. Yaru Zhou and Yu Yang contributed equally to this work.

Authors and Affiliations

  1. Department of Endocrinology, Third Hospital of Hebei Medical University, Shijiazhuang, China

    Yaru Zhou, Yu Yang, Yan Liu, Kuanzhi Liu & Xiaojuan Zhang

  2. Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, China

    Hengrui Chang

  3. College of Life Science, Hebei Normal University, Shijiazhuang, 050051, China

    Yanzhong Chang

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  1. Yaru Zhou
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Contributions

YZ and YY performed most of the experiments; YL, HC, KL, and XZ performed experiments and data analysis; YY wrote the manuscript; YZ, YL, and YC interpreted data and critically revised the manuscript. All authors approved the final manuscript.

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Correspondence to Yaru Zhou or Yanzhong Chang.

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Conflict of interest

Yaru Zhou, Yu Yang, Yan Liu, Hengrui Chang, Kuanzhi Liu, Xiaojuan Zhang, and Yanzhong Chang declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

The experimental procedures were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and were approved by the Animal Care and Use Committee of Hebei Science and Technical Bureau in China.

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Zhou, Y., Yang, Y., Liu, Y. et al. Irp2 Knockout Causes Osteoporosis by Inhibition of Bone Remodeling. Calcif Tissue Int 104, 70–78 (2019). https://doi.org/10.1007/s00223-018-0469-2

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