Osteoblasts induce Ca2+ oscillation-independent NFATc1 activation during osteoclastogenesis

Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8643-8. doi: 10.1073/pnas.0800642105. Epub 2008 Jun 13.


Intercellular cross-talk between osteoblasts and osteoclasts is important for controlling bone remolding and maintenance. However, the precise molecular mechanism by which osteoblasts regulate osteoclastogenesis is still largely unknown. Here, we show that osteoblasts can induce Ca(2+) oscillation-independent osteoclastogenesis. We found that bone marrow-derived monocyte/macrophage precursor cells (BMMs) lacking inositol 1,4,5-trisphosphate receptor type2 (IP(3)R2) did not exhibit Ca(2+) oscillation or differentiation into multinuclear osteoclasts in response to recombinant receptor activator of NF-kappaB ligand/macrophage colony-stimulating factor stimulation. IP(3)R2 knockout BMMs, however, underwent osteoclastogenesis when they were cocultured with osteoblasts or in vivo in the absence of Ca(2+) oscillation. Furthermore, we found that Ca(2+) oscillation-independent osteoclastogenesis was insensitive to FK506, a calcineurin inhibitor. Taken together, we conclude that both Ca(2+) oscillation/calcineurin-dependent and -independent signaling pathways contribute to NFATc1 activation, leading to efficient osteoclastogenesis in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Cell Communication
  • Cell Differentiation
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • Mice
  • Mice, Knockout
  • Models, Biological
  • NF-kappa B / metabolism
  • NFATC Transcription Factors / metabolism*
  • Osteoblasts / metabolism*
  • Osteoclasts / metabolism*
  • RANK Ligand / metabolism
  • Signal Transduction


  • Inositol 1,4,5-Trisphosphate Receptors
  • NF-kappa B
  • NFATC Transcription Factors
  • RANK Ligand
  • Calcium