Ca2+-NFATc1 signaling is an essential axis of osteoclast differentiation

Immunol Rev. 2009 Sep;231(1):241-56. doi: 10.1111/j.1600-065X.2009.00821.x.


Osteoclasts are unique, multinucleated giant cells that decalcify and degrade the bone matrix. They originate from hematopoietic cells and their differentiation is dependent on a tumor necrosis factor (TNF) family cytokine, receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL), as well as macrophage-colony stimulating factor (M-CSF). Recent studies have unveiled the precise molecular mechanism underlying osteoclastogenesis. In particular, the discovery of nuclear factor of activated T cells c1 (NFATc1), the master regulator of osteoclastogenesis, has proven to be a breakthrough in this field. NFATc1 is activated by Ca2+ signaling induced by the activation of the immunoglobulin-like receptor signaling associated with immunoreceptor tyrosine-based activation motif (ITAM)-harboring adapters. The long-lasting Ca2+ oscillation, which is evident during osteoclastogenesis, may ensure the robust induction of NFATc1 through an autoamplification mechanism. Thus, intracellular Ca2+ is a critical attribute of osteoclastogenic signaling. In addition, osteoclasts are exposed to a very high extracellular Ca2+ concentration ([Ca2+]o) in the bone microenvironment and respond to the change in [Ca2+]o by increasing the intracellular Ca2+, which regulates diverse cellular functions. Investigation of the molecular mechanisms underlying the regulation of intracellular Ca2+ dynamics may open up new directions for therapeutic strategies in bone disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Calcium Signaling*
  • Cell Differentiation*
  • Humans
  • Macrophage Colony-Stimulating Factor / metabolism
  • NFATC Transcription Factors / metabolism*
  • Osteoclasts / cytology*
  • Osteoclasts / metabolism*
  • RANK Ligand / metabolism


  • NFATC Transcription Factors
  • RANK Ligand
  • Macrophage Colony-Stimulating Factor