Regulatory mechanism of osteoclastogenesis by RANKL and Wnt signals

Front Biosci (Landmark Ed). 2011 Jan 1;16:21-30. doi: 10.2741/3673.


Osteoclasts develop from monocyte-macrophage lineage cells under the regulation of osteoblasts. Osteoblasts express two cytokines essential for osteoclastogenesis, macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-KappaB ligand (RANKL). Osteoblasts also produce osteoprotegerin (OPG), a decoy receptor for RANKL, which inhibits the interaction between RANKL and RANK, a receptor of RANKL. Bone resorption-stimulating factors act on osteoblasts to regulate RANKL and OPG expression. Nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) is a master transcription factor for osteoclast differentiation. The immunoreceptor tyrosine-based activation motif (ITAM)-mediated signal was discovered as a co-stimulatory signal in RANKL-induced osteoclastogenesis. Wnt proteins activate two pathways: beta-catenin-dependent canonical and beta-catenin-independent noncanonical pathways. Wnt proteins promote differentiation of osteoblasts through the canonical pathway. The canonical pathway in osteoblasts also suppresses osteoclastogenesis through up-regulation of OPG expression and down-regulation of RANKL expression. In contrast, activation of the noncanonical pathway in osteoclast precursors enhances RANKL-induced osteoclastic differentiation. Thus, Wnt signals in osteoblasts and osteoclast precursors play important roles in osteoclastogenesis. This review summarizes the regulatory mechanism of osteoclastogenesis by RANKL and Wnt signals.

Publication types

  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Bone Resorption / physiopathology
  • Cell Differentiation
  • Humans
  • Macrophage Colony-Stimulating Factor / metabolism
  • Membrane Proteins / physiology
  • NFATC Transcription Factors / physiology
  • Osteoclasts / cytology
  • Osteoclasts / physiology*
  • RANK Ligand / physiology*
  • Signal Transduction
  • Wnt Proteins / physiology*


  • Adaptor Proteins, Signal Transducing
  • DCSTAMP protein, human
  • Membrane Proteins
  • NFATC Transcription Factors
  • RANK Ligand
  • Wnt Proteins
  • Macrophage Colony-Stimulating Factor