Endocrinol Metab.  2023 Oct;38(5):504-521. 10.3803/EnM.2023.501.

Nuclear Factor-Kappa B Regulation of Osteoclastogenesis and Osteoblastogenesis

• Boyce BF
• Li J
• Yao Z
• Xing L

• KMID: 2546981
• DOI: http://doi.org/10.3803/EnM.2023.501

Abstract

Maintenance of skeletal integrity requires the coordinated activity of multinucleated bone-resorbing osteoclasts and bone-forming osteoblasts. Osteoclasts form resorption lacunae on bone surfaces in response to cytokines by fusion of precursor cells. Osteoblasts are derived from mesenchymal precursors and lay down new bone in resorption lacunae during bone remodeling. Nuclear factorkappa B (NF-κB) signaling regulates osteoclast and osteoblast formation and is activated in osteoclast precursors in response to the essential osteoclastogenic cytokine, receptor activator of NF-κB ligand (RANKL), which can also control osteoblast formation through RANK-RANKL reverse signaling in osteoblast precursors. RANKL and some pro-inflammatory cytokines, including tumor necrosis factor (TNF), activate NF-κB signaling to positively regulate osteoclast formation and functions. However, these cytokines also limit osteoclast and osteoblast formation through NF-κB signaling molecules, including TNF receptor-associated factors (TRAFs). TRAF6 mediates RANKL-induced osteoclast formation through canonical NF-κB signaling. In contrast, TRAF3 limits RANKL- and TNF-induced osteoclast formation, and it restricts transforming growth factor β (TGFβ)-induced inhibition of osteoblast formation in young and adult mice. During aging, neutrophils expressing TGFβ and C-C chemokine receptor type 5 (CCR5) increase in bone marrow of mice in response to increased NF-κB-induced CC motif chemokine ligand 5 (CCL5) expression by mesenchymal progenitor cells and injection of these neutrophils into young mice decreased bone mass. TGFβ causes degradation of TRAF3, resulting in decreased glycogen synthase kinase-3β/β-catenin-mediated osteoblast formation and age-related osteoporosis in mice. The CCR5 inhibitor, maraviroc, prevented accumulation of TGFβ+/CCR5+ neutrophils in bone marrow and increased bone mass by inhibiting bone resorption and increasing bone formation in aged mice. This paper updates current understanding of how NF-κB signaling is involved in the positive and negative regulation of cytokine-mediated osteoclast and osteoblast formation and activation with a focus on the role of TRAF3 signaling, which can be targeted therapeutically to enhance bone mass.

Keyword

Osteoclasts; Osteoblasts; Aging; Osteoporosis; TNF receptor-associated factor 6; TNF receptor-associated factor 3; Transforming growth factor-beta; Bone resorption; Neutrophils; Receptors, chemokine

Figure

• 

  Fig. 1. Canonical and non-canonical nuclear factor-kappa B (NF-κB) signaling induced by tumor necrosis factor (TNF) and receptor activator of NF-κB ligand (RANKL) in osteoclast precursors. RANKL and TNF induce canonical NF-κB signaling by recruiting TNF receptor-associated factor 6 (TRAF6) and TRAF2/5, respectively, to their receptors to activate a complex consisting of inhibitory NF-κB (IκB) kinase α (IKKα), IKKβ, and IKKγ (NF-κB essential modulator [NEMO]). This complex induces phosphorylation and degradation of IκB-α and the release of p65/p50 heterodimers, which translocate to the nucleus. p65/p50 induce expression of c-Fos and nuclear factor of activated T cells c1 (NFATc1), two other transcription factors necessary for osteoclast precursor differentiation, as well as the inhibitory κB protein, NF-κB p100. In unstimulated cells, p100 binds to RelB to prevent its translocation to the nucleus. RANKL induces the ubiquitination (Ub) and lysosomal degradation of TRAF3, releasing NF-κB-inducing kinase (NIK) to activate (phosphorylate) IKKα, which leads to proteasomal processing of p100 to p52. RelB:p52 heterodimers then go to the nucleus to induce target gene expression. TNF signaling does not degrade TRAF3, and thus NIK is degraded constitutively, leading to the accumulation of p100 in the cytoplasm of osteoclast precursors to limit their differentiation. TAK1, TGFβ-activated kinase-1; cIAP, complex inhibitor of apoptosis.

• 

  Fig. 2. Mouse models with genetically modified nuclear factor-kappa B (NF-κB) activation status in osteoblast lineage cells demonstrating that both canonical and non-canonical NF-κB signaling pathways are involved in osteoblast functions postnatally. Col2, collagen 2; IKK, inhibitory IκB kinase; OB, osteoblast; Bglap2, bone gamma-carboxyglutamate protein 2; Prx1, paired related homeobox 1; TRAF3, TNF receptor-associated factor 3; NIK, NF-κB-inducing kinase; MSC, mesenchymal stem cell; Osx, osterix.

• 

  Fig. 3. Tumor necrosis factor (TNF) receptor-associated factor 3 (TRAF3) functions in osteoclast and osteoblast precursors in bone resorption and bone formation. In aged mice, increased levels of receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL) induce (1) TRAF3 ubiquitination and subsequent lysosomal degradation in osteoclast (OC) precursors to stimulate bone resorption through NF-κB signaling. As a result, (2) transforming growth factor β1 (TGFβ1) is released from bone matrix and activated in the acid environment in resorption lacunae. Activated TGFβ1 binds to its receptor complex on mesenchymal progenitor cells (MPCs) to which TRAF3 is recruited and subsequently ubiquitinated and degraded in lysosomes. As a result, (3) NF-κB signaling is activated and both RelA and RelB bind to the RANKL promoter to further promote RANKL production, enhancing bone resorption. In young and adult mice, TRAF3 inhibits glycogen synthase kinase-3β (GSK3β) activation in MPCs to prevent β-catenin degradation, allowing β-catenin accumulation and nuclear translocation to maintain osteoblast [OB] differentiation). In aged mice, TRAF3 degradation also leads to (4) increased NF-κB-induced secretion of CC motif chemokine ligand 5 (CCL5) by MPCs, which attracts increased numbers of TGFβ1/C-C chemokine receptor type 3 (CCR3)-expressing neutrophils (TCN) to the bone marrow where they release TGFβ, leading to further degradation of TRAF3 and (5) phosphorylation of GSK3β on T216. This phosphorylation mediates degradation of β-catenin, leading to (6) inhibition of OB precursor differentiation, increased production of osteoprotegerin (OPG) and decreased bone mass.

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