Extracellular Iron is a Modulator of the Differentiation of Osteoclast Lineage Cells

Calcif Tissue Int. 2016 Mar;98(3):275-83. doi: 10.1007/s00223-015-0087-1. Epub 2015 Nov 28.


Osteoclasts originate from the hematopoietic stem cell and share a differentiation pathway with the cells of the monocyte/macrophage lineages. Development and activation of osteoclasts, and as a consequence regulation of bone resorption, depend on two growth factors: macrophage colony-stimulating factor and receptor activator of NF-κB ligand. Furthermore, cell development and activity are modulated by a microenvironment composed of cytokines and growth factors and of the extracellular matrix. Membrane transporters are a means for cells to interact with their environment. Within this study, the expression of proteins regulating cellular iron homeostasis in osteoclast-like cells grown from bone marrow-derived progenitors was compared to the expression of this set of proteins by monocyte/macrophage lineage cells. In differentiating osteoclasts, levels of transcripts encoding transferrin receptor 1 and divalent metal transporter 1 (Slc11A2) were increased, while levels of transcripts encoding ferroportin (Slc40A1) and natural resistance-associated macrophage protein 1 (Slc11A1) were decreased. Supplementation of the culture media with exogenous iron led to an increase in the proliferation of osteoclast progenitor cells and to the expression of a macrophage-like phenotype, while the development of osteoclasts was reduced. Upon transfer of mature OC onto a CaP substrate, iron depletion of the medium with the Fe(3+)-chelator Deferoxamine Mesylate decreased CaP dissolution by ~30 %, which could be restored by addition of exogenous iron. During the 24 h of the assay, no effects were observed on total TRAP activity. The data demonstrate transcriptional regulation of the components of cellular iron transporters during OC development and suggests that iron homeostasis may contribute to fine-tuning of the RANKL-induced OC development.

Keywords: DMT1; Ferroportin; Osteoclast; RANKL; TfR1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology
  • Cation Transport Proteins / metabolism
  • Cell Differentiation
  • Cell Lineage
  • Cell Proliferation
  • Culture Media / chemistry
  • Cytokines / metabolism
  • Hematopoietic Stem Cells / cytology
  • Homeostasis
  • Iron / chemistry*
  • Macrophages / cytology
  • Mice
  • Mice, Inbred C57BL
  • Osteoclasts / cytology*
  • Phenotype
  • RANK Ligand / metabolism
  • Receptors, Transferrin / metabolism
  • Transcription, Genetic


  • Cation Transport Proteins
  • Culture Media
  • Cytokines
  • RANK Ligand
  • Receptors, Transferrin
  • Tfrc protein, mouse
  • metal transporting protein 1
  • natural resistance-associated macrophage protein 1
  • solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2
  • Iron