Akane Yamada1,2, Maiko Kawasaki1, Yasuo Miake3, Yurie Yamada1,4, James Blackburn5, Katsushige Kawasaki1,4, Supaluk Trakanant1, Takahiro Nagai1,2, Jun Nihara1, Takehisa Kudo1, Fumiya Meguro1, Ruth Schmidt-Ullrich6, Bigang Liu7, Yinling Hu8, Angustias Page9, Ángel Ramírez9, Paul T Sharpe5, Takeyasu Maeda4, Ritsuo Takagi2, Atsushi Ohazama1. 1. Division of Oral Anatomy, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan. 2. Division of Oral and Maxillofacial Surgery, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan. 3. Department of Oral Anatomy, School of Dental Medicine, Tsurumi University, Tsurumi, Japan. 4. Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Research Center for Advanced Oral Science, Niigata University, Niigata, Japan. 5. Centre for Craniofacial and Regenerative Biology, King's College London, London, UK. 6. Department of Signal Transduction in Tumor Cells, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. 7. University of Texas MD Anderson Cancer Center, Smithville, TX, USA. 8. Center for Cancer Research, National Cancer Institute, Frederick, MD, USA. 9. Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Instituto de Investigación Sanitaria Hospital12 de Octubre (imas12), CIBERONC, Madrid, Spain.
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.
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.
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