Overactivation of the NF‐κB pathway impairs molar enamel formation

Abstract

Objective Hypohidrotic ectodermal dysplasia (HED) is a hereditary disorder characterized by abnormal structures and functions of the ectoderm‐derived organs, including teeth. HED patients exhibit a variety of dental symptoms, such as hypodontia. Although disruption of the EDA/EDAR/EDARADD/NF‐κB pathway is known to be responsible for HED, it remains unclear whether this pathway is involved in the process of enamel formation. Experimental subjects and methods To address this question, we examined the mice overexpressing Ikkβ (an essential component required for the activation of NF‐κB pathway) under the keratin 5 promoter (K5‐Ikkβ). Results Upregulation of the NF‐κB pathway was confirmed in the ameloblasts of K5‐Ikkβ mice. Premature abrasion was observed in the molars of K5‐Ikkβ mice, which was accompanied by less mineralized enamel. However, no significant changes were observed in the enamel thickness and the pattern of enamel rods in K5‐Ikkβ mice. Klk4 expression was significantly upregulated in the ameloblasts of K5‐Ikkβ mice at the maturation stage, and the expression of its substrate, amelogenin, was remarkably reduced. This suggests that abnormal enamel observed in K5‐Ikkβ mice was likely due to the compromised degradation of enamel protein at the maturation stage. Conclusion Therefore, we could conclude that the overactivation of the NF‐κB pathway impairs the process of amelogenesis.

ERAS, a Member of the Ras Superfamily, Acts as an Oncoprotein in the Mammary Gland

“…Nrf2 absence in mice leads to an aberrant iron deposition in the papillary layer cells of the enamel organ and to altered ameloblasts, causing a loss of iron deposition on the enamel surface [ 38 ]. As the K5 promoter that we have used to direct the expression of ERAS is active in ameloblasts [ 39 , 40 , 41 ], it is conceivable that ERAS expression in this cell type may alter ameloblast functioning, resulting in a defective enamel iron deposition and discoloration.…”

The EDA/EDAR/NF-κB pathway in non-syndromic tooth agenesis: A genetic perspective

“…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 ).…”

“…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 ). Studies have suggested that NF-κB plays an essential role in regulating the expression of proteins related to amelogenesis and can impair the enamel formation ( Liang et al, 2019 ; Yamada et al, 2020 ).…”