Critical Roles of NF-κB Signaling Molecules in Bone Metabolism Revealed by Genetic Mutations in Osteopetrosis

Abstract

The nuclear factor-κB (NF-κB) transcription factor family consists of five related proteins, RelA (p65), c-Rel, RelB, p50/p105 (NF-κB1), and p52/p100 (NF-κB2). These proteins are important not only for inflammation and the immune response but also for bone metabolism. Activation of NF-κB occurs via the classic and alternative pathways. Inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, activate the former, and cytokines involved in lymph node formation, such as receptor activator of NF-κB ligand (RANKL) and CD40L, activate the latter. p50 and p52 double-knockout mice revealed severe osteopetrosis due to the total lack of osteoclasts, which are specialized cells for bone resorption. This finding suggests that the activation of NF-κB is required for osteoclast differentiation. The NF-κB signaling pathway is controlled by various regulators, including NF-κB essential modulator (NEMO), which is encoded by the IKBKG gene. In recent years, mutant forms of the IKBKG gene have been reported as causative genes of osteopetrosis, lymphedema, hypohidrotic ectodermal dysplasia, and immunodeficiency (OL-EDA-ID). In addition, a mutation in the RELA gene, encoding RelA, has been reported for the first time in newborns with high neonatal bone mass. Osteopetrosis is characterized by a diffuse increase in bone mass, ranging from a lethal form observed in newborns to an asymptomatic form that appears in adulthood. This review describes the genetic mutations in NF-κB signaling molecules that have been identified in patients with osteopetrosis.

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“…Research has demonstrated that both the IKKα and β subunits exhibit catalytic activity, while NEMO/IKKγ is involved in the recruitment of IκBs ( Barczewski et al, 2019 ). Moreover, IKKβ has been identified as the predominant kinase responsible for IκB phosphorylation ( Yamada et al, 2020 ; Jimi and Katagiri, 2022 ). The phosphorylation of IκBs triggers their polyubiquitination, proteasomal degradation by the 26s proteasome, and eventually the release of NF-κB transcription factor into the nucleus ( Chen and Greene, 2004 ).…”

“…The phosphorylation of IκBs triggers their polyubiquitination, proteasomal degradation by the 26s proteasome, and eventually the release of NF-κB transcription factor into the nucleus ( Chen and Greene, 2004 ). NF-κB is a homo or heterodimer that can be formed from different combinations of RelA (p65), c-Rel, RelB, p50/p105 (NF-κB1), and p52/p100 (NF-κB2) ( Courtney et al, 2005 ; Yamada et al, 2020 ; Jimi and Katagiri, 2022 ). After the nuclear translocation of NF-κB, it induces the expression of genes essential for initiating and differentiating skin appendages such as hair, teeth, and sweat glands ( Figure 2 ).…”