Critical Roles of NF-κB Signaling Molecules in Bone Metabolism Revealed by Genetic Mutations in Osteopetrosis
<p>Schematic representation of the NF-κB family proteins. Members of the NF-κB protein family are shown. The total number of amino acids in each protein is indicated on the right. Presumed sites of cleavage in p105 (amino acid 433) and p100 (amino acid 447) are indicated by dotted lines. RHD: Rel homology domain; TAD: transcriptional activation domain [<a href="#B8-ijms-23-07995" class="html-bibr">8</a>]; LZ: leucine zipper; GRR: glycine-rich repeat; ANK: ankyrin repeat. An arrow indicates the position of a genetic mutation associated with osteopetrosis.</p> "> Figure 2
<p>Two different NF-κB signaling pathways. The classic (canonical) pathway (<b>left</b>) is activated by a large number of agonists, such as TNF-α, IL-1, lipopolysaccharide, and T-cell receptors. The activation of this pathway depends on the inhibitor of the κB (IκB) kinase (IKK) complex (IKKα/β and NEMO), which phosphorylates IκBα (Ser32, 36) to induce rapid degradation. This pathway is essential for immune responses, inflammation, tumorigenesis, and cell survival. The alternative (noncanonical) pathway (<b>right</b>) is activated by a limited number of agonists, which are involved in secondary lymphoid organogenesis. This pathway requires NF-κB-inducing kinase (NIK) and IKKα. These kinases induce the slow processing of p100 to generate p52, resulting in the dimerization and activation of the p52/RelB heterodimer. The activation of NF-κB signaling stimulates osteoclastic bone resorption and suppresses bone formation.</p> "> Figure 3
<p>Schematic structure of NEMO and the genetic mutations in the <span class="html-italic">IKBKG</span> gene associated with osteopetrosis. The nucleotide and amino acid sequences of the <span class="html-italic">IKBKG</span> gene and the NEMO protein, respectively, are indicated in black (normal), blue (c.1,259A > G; p.X420W) [<a href="#B50-ijms-23-07995" class="html-bibr">50</a>], red (c.1,182_1,183del_insTT; OL-EDA-ID) [<a href="#B51-ijms-23-07995" class="html-bibr">51</a>], and green (c.1,238A > G; p.H413R) [<a href="#B52-ijms-23-07995" class="html-bibr">52</a>]. Dots indicate deletions, and open boxes indicate “stop codons”. CC: coiled-coil domain; NUB: NEMO ubiquitin binding; LZ: leucine zipper; ZF: zinc finger.</p> ">
Abstract
:1. Introduction
2. Regulatory Mechanism of NF-κB Signaling
3. NF-κB Signaling Regulates Bone Metabolism
3.1. NF-κB Functions in Physiological Bone Resorption
3.2. Molecular Mechanisms of Osteoclast Differentiation Regulated by NF-kB
3.3. NF-κB Negatively Regulates Bone Formation
3.4. Genetic Mutations of the NF-κB Signaling Molecule in Osteopetrosis
4. Osteopetrosis
5. Structure and Function of NEMO and NEMO-Related Diseases
5.1. Incontinentia Pigmenti: IP
5.2. EDA-ID
5.3. Osteopetrosis, Lymphedema, Hypohidrotic ectodermal Dysplasia and Immunodeficiency (OL-HED-ID)
5.3.1. p.X420W
5.3.2. c.1,182_1,183TT Deletion
5.3.3. c.1,238A > G (p.H413R)
6. Neonatal High Bone Mass (HBM) Caused by RelA Mutation
7. Conclusions and Perspectives
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Jimi, E.; Katagiri, T. Critical Roles of NF-κB Signaling Molecules in Bone Metabolism Revealed by Genetic Mutations in Osteopetrosis. Int. J. Mol. Sci. 2022, 23, 7995. https://doi.org/10.3390/ijms23147995
Jimi E, Katagiri T. Critical Roles of NF-κB Signaling Molecules in Bone Metabolism Revealed by Genetic Mutations in Osteopetrosis. International Journal of Molecular Sciences. 2022; 23(14):7995. https://doi.org/10.3390/ijms23147995
Chicago/Turabian StyleJimi, Eijiro, and Takenobu Katagiri. 2022. "Critical Roles of NF-κB Signaling Molecules in Bone Metabolism Revealed by Genetic Mutations in Osteopetrosis" International Journal of Molecular Sciences 23, no. 14: 7995. https://doi.org/10.3390/ijms23147995