Molecular mechanisms of triggering, amplifying and targeting RANK signaling in osteoclasts
- 1 January 2012
- journal article
- Published by Baishideng Publishing Group Inc. in World Journal of Orthopedics
- Vol. 3 (11), 167-74
- https://doi.org/10.5312/wjo.v3.i11.167
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 immediate-early 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 RANKL-induced 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, osteoblast-dependent 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 differentiationKeywords
This publication has 77 references indexed in Scilit:
- MicroRNA control of bone formation and homeostasisNature Reviews Endocrinology, 2012
- A Long Noncoding RNA Controls Muscle Differentiation by Functioning as a Competing Endogenous RNACell, 2011
- Matrix-embedded cells control osteoclast formationNature Medicine, 2011
- Blimp1-mediated repression of negative regulators is required for osteoclast differentiationProceedings of the National Academy of Sciences, 2010
- Interferon regulatory factor-8 regulates bone metabolism by suppressing osteoclastogenesisNature Medicine, 2009
- Human Osteoclast-Poor Osteopetrosis with Hypogammaglobulinemia due to TNFRSF11A (RANK) MutationsAmerican Journal of Human Genetics, 2008
- Osteoblasts induce Ca 2+ oscillation-independent NFATc1 activation during osteoclastogenesisProceedings of the National Academy of Sciences, 2008
- Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systemsNature Reviews Immunology, 2007
- Site-specific Lys-63-linked Tumor Necrosis Factor Receptor-associated Factor 6 Auto-ubiquitination Is a Critical Determinant of IκB Kinase ActivationJournal of Biological Chemistry, 2007
- RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-βNature, 2002