Ionizing Radiation Exacerbates the Bone Loss Induced by Iron Overload in Mice


Patients with radiotherapy are at significant risks of bone loss and fracture. On the other hand, osteoporosis often occurs in disorders characterized by iron overload. Either ionizing radiation (IR) or iron overload alone has detrimental effects on bone metabolism, but their combined effects are not well defined. In this study, we evaluated the effects of IR on bone loss in an iron-overload mouse model induced by intraperitoneal injection of ferric ammonium citrate (FAC). In the present study, we found that IR additively aggravated iron overload induced by FAC injections. Iron overload stimulated hepcidin synthesis, while IR had an inhibitory effect and even inhibited the stimulatory effects of iron overload. Micro-CT analysis demonstrated that the loss of bone mineral density and bone volume, and the deterioration of bone microarchitecture were greatest in combined treatment group. Iron altered the responses of bone cells to IR. Iron enhanced the responses of osteoclasts to IR with elevated osteoclast differentiation, but did not affect osteoblast differentiation. Our study indicates that IR and iron in combination lead to a more severe impact on the bone homeostasis when compared with their respective effects. IR aggravated iron overload induced bone loss by heightened bone resorption relative to formation. The addictive effects may be associated with the exacerbated iron accumulation and osteoclast differentiation.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6



Alkaline phosphatase


bone mineral density


Bone marrow macrophages


Bone sialoprotein


Bone volume fraction


Collagen 1


Cathepsin K


Dentin matrix acidic phosphoprotein 1


Ferric ammonium citrate


Glyceraldehyde-3-phosphate dehydrogenase


Hepcidin antimicrobial peptide


Ionizing radiation


Mineral apposition rate


Macrophage colony stimulating factor


Matrix metallopeptidase 9

Opn :



Receptor activator for nuclear factor-κB ligand


Runt-related transcription factor 2


Trabecular thickness


Trabecular separation


Trabecular number


Total body irradiation


Tartrate-resistant acid phosphatase


Vacuolar-type H (+)-ATPase


  1. 1.

    Abbaspour N, Hurrell R, Kelishadi R (2014) Review on iron and its importance for human health. J Res Med Sci 19(2):164–174

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Balogh E, Paragh G, Jeney V (2018) Influence of iron on bone homeostasis. Pharmaceuticals 11(4):107

    CAS  Article  Google Scholar 

  3. 3.

    Kocpinar EF, Gonul Baltaci N, Ceylan H, Kalin SN, Erdogan O, Budak H (2019) Effect of a prolonged dietary iron intake on the gene expression and activity of the testicular antioxidant defense system in rats. Biol Trace Elem Res.

  4. 4.

    Budak H, Gonul N, Ceylan H et al (2014) Impact of long term Fe(3)(+) toxicity on expression of glutathione system in rat liver. Environ Toxicol Pharmacol 37(1):365–370

    CAS  Article  Google Scholar 

  5. 5.

    Balogh E, Paragh G, Jeney V (2018) Influence of iron on bone homeostasis. Pharmaceuticals (Basel) 11(4):E107

    Article  Google Scholar 

  6. 6.

    Mitchell F (2012) High body iron stores lead to bone loss. Nat Rev Endocrinol 8(9):506

    Article  Google Scholar 

  7. 7.

    Ishii KA, Fumoto T, Iwai K et al (2009) Coordination of PGC-1beta and iron uptake in mitochondrial biogenesis and osteoclast activation. Nat Med 15(3):259–266

    CAS  Article  Google Scholar 

  8. 8.

    Jeney V (2017) Clinical impact and cellular mechanisms of iron overload-associated bone loss. Front Pharmacol 8:77

    Article  Google Scholar 

  9. 9.

    Kim BJ, Ahn SH, Bae SJ et al (2012) Iron overload accelerates bone loss in healthy postmenopausal women and middle-aged men: a 3-year retrospective longitudinal study. J Bone Miner Res 27(11):2279–2290

    CAS  Article  Google Scholar 

  10. 10.

    Zhang J, Qiu X, Xi K et al (2018) Therapeutic ionizing radiation induced bone loss: a review of in vivo and in vitro findings. Connect Tissue Res 59(6):509–522

    Article  Google Scholar 

  11. 11.

    Zhang J, Wang Z, Wu A et al (2017) Differences in responses to X-ray exposure between osteoclast and osteoblast cells. J Radiat Res 58(6):791–802

    CAS  Article  Google Scholar 

  12. 12.

    Morgan JL, Ritchie LE, Crucian BE (2014) Increased dietary iron and radiation in rats promote oxidative stress, induce localized and systemic immune system responses, and alter colon mucosal environment. FASEB J 28(3):1486–1498

    CAS  Article  Google Scholar 

  13. 13.

    Nelson JM, Stevens RG (1992) Ferritin-iron increases killing of Chinese hamster ovary cells by X-irradiation. Cell Prolif 25(6):579–585

    CAS  Article  Google Scholar 

  14. 14.

    Theriot CA, Westby CM, Morgan JLL et al (2016) High dietary iron increases oxidative stress and radiosensitivity in the rat retina and vasculature after exposure to fractionated gamma radiation. NPJ Microgravity 2:16014

    Article  Google Scholar 

  15. 15.

    Xiao W, Beibei F, Guangsi S et al (2015) Iron overload increases osteoclastogenesis and aggravates the effects of ovariectomy on bone mass. J Endocrinol 226(3):121–134

    CAS  Article  Google Scholar 

  16. 16.

    Zhang J, Zheng L, Wang Z et al (2019) Lowering iron level protects against bone loss in focally irradiated and contralateral femurs through distinct mechanisms. Bone 120:50–60

    CAS  Article  Google Scholar 

  17. 17.

    Zhang J, Meng X, Ding C et al (2018) Effects of static magnetic fields on bone microstructure and mechanical properties in mice. Electromagn Biol Med 37(2):76–83

    Article  Google Scholar 

  18. 18.

    Zhang J, Meng X, Ding C et al (2017) Regulation of osteoclast differentiation by static magnetic fields. Electromagn Biol Med 36(1):8–19

    CAS  PubMed  Google Scholar 

  19. 19.

    Zhang J, Ding C, Shang P (2014) Alterations of mineral elements in osteoblast during differentiation under hypo, moderate and high static magnetic fields. Biol Trace Elem Res 162(1-3):153–157

    CAS  Article  Google Scholar 

  20. 20.

    Girelli D, Nemeth E, Swinkels DW (2016) Hepcidin in the diagnosis of iron disorders. Blood 127(23):2809–2813

    CAS  Article  Google Scholar 

  21. 21.

    Yoshiyama M, Okamoto Y, Izumi S et al (2019) Graphite furnace atomic absorption spectrometric evaluation of iron excretion in mouse urine caused by whole-body gamma irradiation. Biol Trace Elem Res 191(1):149–158

    CAS  Article  Google Scholar 

  22. 22.

    Xu Z, Sun W, Li Y et al (2017) The regulation of iron metabolism by hepcidin contributes to unloading-induced bone loss. Bone 94:152–161

    CAS  Article  Google Scholar 

  23. 23.

    Gehrke SG, Herrmann T, Kulaksiz H et al (2005) Iron stores modulate hepatic hepcidin expression by an HFE-independent pathway. Digestion 72(1):25–32

    CAS  Article  Google Scholar 

  24. 24.

    Ono T, Nakashima T (2018) Recent advances in osteoclast biology. Histochem Cell Biol 149(4):325–341

    CAS  Article  Google Scholar 

  25. 25.

    Chen M, Huang Q, Xu W et al (2014) Low-dose X-ray irradiation promotes osteoblast proliferation, differentiation and fracture healing. PLoS One 9(8):e104016

    Article  Google Scholar 

  26. 26.

    Szymczyk KH, Shapiro IM, Adams CS (2004) Ionizing radiation sensitizes bone cells to apoptosis. Bone 34(1):148–156

    CAS  Article  Google Scholar 

  27. 27.

    Zhang J, Hu W, Ding C et al (2019) Deferoxamine inhibits iron-uptake stimulated osteoclast differentiation by suppressing electron transport chain and MAPKs signaling. Toxicol Lett 313:50–59

    CAS  Article  Google Scholar 

  28. 28.

    Keenawinna L, Oest ME, Mann KA et al (2013) Zoledronic acid prevents loss of trabecular bone after focal irradiation in mice. Radiat Res 180(1):89–99

    CAS  Article  Google Scholar 

  29. 29.

    Willey JS, Livingston EW, Robbins ME et al (2010) Risedronate prevents early radiation-induced osteoporosis in mice at multiple skeletal locations. Bone 46(1):101–111

    CAS  Article  Google Scholar 

  30. 30.

    Schreurs AS, Shirazi-Fard Y, Shahnazari M et al (2016) Dried plum diet protects from bone loss caused by ionizing radiation. Sci Rep 6:21343

    CAS  Article  Google Scholar 

Download references


This study was funded by the National Natural Science Foundation of China (31600674), the Science and Technology Fund of Guizhou Health Commission (gzwjkj2019-1-226), and doctoral funds of Guizhou University of Traditional Chinese Medicine ([2019]44).

Author information



Corresponding author

Correspondence to Jian Zhang.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving animals were in accordance with the ethical standards of Guizhou University of Traditional Chinese Medicine at which the studies were conducted (Animal Ethics and Welfare Committee at Guizhou University of Traditional Chinese Medicine; Permit No. GZY20190005).

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zhang, J., Qiao, P., Yao, G. et al. Ionizing Radiation Exacerbates the Bone Loss Induced by Iron Overload in Mice. Biol Trace Elem Res 196, 502–511 (2020).

Download citation


  • Iron overload
  • Ionizing radiation
  • Bone loss
  • Osteoblast
  • Osteoclast