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

Abstract

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.

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Abbreviations

ALP:

Alkaline phosphatase

BMD:

bone mineral density

BMMs:

Bone marrow macrophages

Bsp:

Bone sialoprotein

BV/TV:

Bone volume fraction

Col1:

Collagen 1

Ctsk:

Cathepsin K

Dmp1:

Dentin matrix acidic phosphoprotein 1

FAC:

Ferric ammonium citrate

Gapdh:

Glyceraldehyde-3-phosphate dehydrogenase

Hamp:

Hepcidin antimicrobial peptide

IR:

Ionizing radiation

MAR:

Mineral apposition rate

M-CSF:

Macrophage colony stimulating factor

Mmp9:

Matrix metallopeptidase 9

Opn :

Osteopontin

RANKL:

Receptor activator for nuclear factor-κB ligand

Runx2:

Runt-related transcription factor 2

Tb.Th.:

Trabecular thickness

Th.Sp.:

Trabecular separation

Tb.N.:

Trabecular number

TBI:

Total body irradiation

TRAP:

Tartrate-resistant acid phosphatase

V-ATPase:

Vacuolar-type H (+)-ATPase

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Funding

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).

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Correspondence to Jian Zhang.

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The authors declare that they have no conflict of interest.

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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).

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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). https://doi.org/10.1007/s12011-019-01929-7

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Keywords

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