Endocrinol Metab.  2015 Mar;30(1):35-44. 10.3803/EnM.2015.30.1.35.

NF-kappaB-Mediated Regulation of Osteoclastogenesis

  • 1Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA. Brendan_Boyce@urmc.rochester.edu


Osteoclasts are multinucleated cells formed mainly on bone surfaces in response to cytokines by fusion of bone marrow-derived myeloid lineage precursors that circulate in the blood. Major advances in understanding of the molecular mechanisms regulating osteoclast formation and functions have been made in the past 20 years since the discovery that their formation requires nuclear factor-kappa B (NF-kappaB) signaling and that this is activated in response to the essential osteoclastogenic cytokine, receptor activator of NF-kappaB ligand (RANKL), which also controls osteoclast activation to resorb (degrade) bone. These studies have revealed that RANKL and some pro-inflammatory cytokines, including tumor necrosis factor, activate NF-kappaB and downstream signaling, including c-Fos and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), and inhibition of repressors of NFATc1 signaling, to positively regulate osteoclast formation and functions. However, these cytokines also activate NF-kappaB signaling that can limit osteoclast formation through the NF-kappaB signaling proteins, TRAF3 and p100, and the suppressors of c-Fos/NFATc1 signaling, IRF8, and RBP-J. This paper reviews current understanding of how NF-kappaB signaling is involved in the positive and negative regulation of cytokine-mediated osteoclast formation and activation.


NF-kappa B; Osteoclasts; RANK ligand; Tumor necrosis factor; TNF receptor-associated factor 3; NF-kappa B kinase

MeSH Terms

NF-kappa B
NFATC Transcription Factors
RANK Ligand
Receptor Activator of Nuclear Factor-kappa B
TNF Receptor-Associated Factor 3
Tumor Necrosis Factor-alpha
NF-kappa B
NFATC Transcription Factors
RANK Ligand
Receptor Activator of Nuclear Factor-kappa B
TNF Receptor-Associated Factor 3
Tumor Necrosis Factor-alpha


  • Fig. 1 Canonical and non-canonical nuclear factor-kappa B (NF-κB) signaling induced by receptor activator of NF-κB ligand (RANKL) and tumor necrosis factor (TNF). RANKL and TNF induce canonical signaling by recruiting TNF receptor (TNFR)-associated factor 6 (TRAF6) and TRAF2/5, respectively, to their receptors to activate a complex consisting of IκB kinase (IKK)-α, IKK-β and IKK-γ (NF-κB essential modulator, NEMO), which induces phosphorylation and degradation of IκB-α and the release of p65/p50 heterodimers, which translocate to the nucleus. This induces expression of c-Fos and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), two other transcription factors necessary for osteoclast precursor differentiation, as well as the inhibitory κB protein, NF-κB p100. In un-stimulated cells, p100 binds to RelB to prevent its translocation to the nucleus. RANKL induces the ubiquitination and lysosomal degradation of TRAF3 through TRAF2/cellular inhibitor of apoptosis 1/2 (cIAP1/2), releasing NF-κB-inducing kinase (NIK) to activate (phosphorylate) IKK-α, which leads to proteasomal processing of p100 to p52; RelB:p52 heterodimers then go to the nucleus to induce target gene expression. TNF does not degrade TRAF3, and thus NIK is degraded, leading to the accumulation of p100 in the cytoplasm of osteoclast precursors to limit their differentiation [3,4].


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