Molecular mechanisms of triggering, amplifying and targeting RANK signaling in osteoclasts

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Abstract

Osteoclast differentiation depends on receptor activator of nuclear factor-κB (RANK) signaling, which can be divided into triggering, amplifying and targeting phases based on how active the master regulator nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) is. The triggering phase is characterized by immediateearly RANK signaling induced by RANK ligand (RANKL) stimulation mediated by three adaptor proteins, tumor necrosis factor receptor-associated factor 6, Grb- 2-associated binder-2 and phospholipase C (PLC)γ2, leading to activation of IκB kinase, mitogen-activated protein kinases and the transcription factors nuclear factor (NF)-κB and activator protein-1 (AP-1). Mice lacking NF-κB p50/p52 or the AP-1 subunit c-Fos (encoded by Fos) exhibit severe osteopetrosis due to a differentiation block in the osteoclast lineage. The amplification phase occurs about 24 h later in a RANKLinduced osteoclastogenic culture when Ca2+ oscillation starts and the transcription factor NFATc1 is abundantly produced. In addition to Ca2+ oscillation-dependent nuclear translocation and transcriptional auto-induction of NFATc1, a Ca2+ oscillation-independent, osteoblastdependent mechanism stabilizes NFATc1 protein in differentiating osteoclasts. Osteoclast precursors lacking PLCγ2, inositol-1,4,5-trisphosphate receptors, regulator of G-protein signaling 10, or NFATc1 show an impaired transition from the triggering to amplifying phases. The final targeting phase is mediated by activation of numerous NFATc1 target genes responsible for cell-cell fusion and regulation of bone-resorptive function. This review focuses on molecular mechanisms for each of the three phases of RANK signaling during osteoclast differentiation.

Original languageEnglish
Pages (from-to)167-174
Number of pages8
JournalWorld Journal of Orthopaedics
Volume3
Issue number11
DOIs
Publication statusPublished - 2012

Fingerprint

NFATC Transcription Factors
Osteoclasts
Transcription Factor AP-1
Transcription Factors
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
GTP-Binding Protein Regulators
RANK Ligand
Osteopetrosis
Inositol 1,4,5-Trisphosphate Receptors
Cell Fusion
Protein Subunits
Type C Phospholipases
Cytoplasmic and Nuclear Receptors
Mitogen-Activated Protein Kinases
Phosphotransferases
Bone and Bones
Genes

Keywords

  • C-Fos
  • Ca oscillation
  • Immunoreceptor tyrosine-based activation motif
  • Nuclear factor of activated T-cells cytoplasmic 1
  • Receptor activator of nuclear factor-κB ligand
  • Tumor necrosis factor receptor-associated factor 6

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine

Cite this

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title = "Molecular mechanisms of triggering, amplifying and targeting RANK signaling in osteoclasts",
abstract = "Osteoclast differentiation depends on receptor activator of nuclear factor-κB (RANK) signaling, which can be divided into triggering, amplifying and targeting phases based on how active the master regulator nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) is. The triggering phase is characterized by immediateearly RANK signaling induced by RANK ligand (RANKL) stimulation mediated by three adaptor proteins, tumor necrosis factor receptor-associated factor 6, Grb- 2-associated binder-2 and phospholipase C (PLC)γ2, leading to activation of IκB kinase, mitogen-activated protein kinases and the transcription factors nuclear factor (NF)-κB and activator protein-1 (AP-1). Mice lacking NF-κB p50/p52 or the AP-1 subunit c-Fos (encoded by Fos) exhibit severe osteopetrosis due to a differentiation block in the osteoclast lineage. The amplification phase occurs about 24 h later in a RANKLinduced osteoclastogenic culture when Ca2+ oscillation starts and the transcription factor NFATc1 is abundantly produced. In addition to Ca2+ oscillation-dependent nuclear translocation and transcriptional auto-induction of NFATc1, a Ca2+ oscillation-independent, osteoblastdependent mechanism stabilizes NFATc1 protein in differentiating osteoclasts. Osteoclast precursors lacking PLCγ2, inositol-1,4,5-trisphosphate receptors, regulator of G-protein signaling 10, or NFATc1 show an impaired transition from the triggering to amplifying phases. The final targeting phase is mediated by activation of numerous NFATc1 target genes responsible for cell-cell fusion and regulation of bone-resorptive function. This review focuses on molecular mechanisms for each of the three phases of RANK signaling during osteoclast differentiation.",
keywords = "C-Fos, Ca oscillation, Immunoreceptor tyrosine-based activation motif, Nuclear factor of activated T-cells cytoplasmic 1, Receptor activator of nuclear factor-κB ligand, Tumor necrosis factor receptor-associated factor 6",
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KW - Receptor activator of nuclear factor-κB ligand

KW - Tumor necrosis factor receptor-associated factor 6

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