Nuclear factor kappa B (NF-κB) signaling plays critical roles in many physiological and pathological processes, including regulating organogenesis. Down-regulation of NF-κB signaling during development results in hypohidrotic ectodermal dysplasia. The roles of NF-κB signaling in tooth development, however, are not fully understood. We examined mice overexpressing IKKβ, an essential component of the NF-κB pathway, under keratin 5 promoter (K5-Ikkβ). K5-Ikkβ mice showed supernumerary incisors whose formation was accompanied by up-regulation of canonical Wnt signaling. Apoptosis that is normally observed in wild-type incisor epithelium was reduced in K5-Ikkβ mice. The supernumerary incisors in K5-Ikkβ mice were found to phenocopy extra incisors in mice with mutations of Wnt inhibitor, Wise. Excess NF-κB activity thus induces an ectopic odontogenesis program that is usually suppressed under physiological conditions.

• MeSH
• Ameloblasts cytology   MeSH
• Amelogenin analysis   MeSH
• Apoptosis physiology   MeSH
• Epithelium embryology   MeSH
• Phenotype MeSH
• Keratin-15 genetics   MeSH
• I-kappa B Kinase physiology   MeSH
• Bone Morphogenetic Proteins genetics   MeSH
• Microradiography methods   MeSH
• Mutation genetics   MeSH
• Mice, Mutant Strains MeSH
• Mice MeSH
• NF-kappa B physiology   MeSH
• Odontogenesis physiology   MeSH
• Promoter Regions, Genetic genetics   MeSH
• Hedgehog Proteins physiology   MeSH
• Receptors, Cell Surface physiology   MeSH
• X-Ray Microtomography methods   MeSH
• Incisor abnormalities   embryology   MeSH
• Wnt Signaling Pathway genetics   physiology   MeSH
• Imaging, Three-Dimensional methods   MeSH
• Dental Enamel cytology   MeSH
• Tooth Germ abnormalities   embryology   MeSH
• Tooth, Supernumerary etiology   genetics   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Iron is both an essential and a potentially toxic element, and its systemic homeostasis is controlled by the iron hormone hepcidin. Hepcidin binds to the cellular iron exporter ferroportin, causes its degradation, and thereby diminishes iron uptake from the intestine and the release of iron from macrophages. Given that hepcidin-resistant ferroportin mutant mice show exocrine pancreas dysfunction, we analysed pancreata of aging hepcidin knockout (KO) mice. Hepcidin and Hfe KO mice were compared with wild-type (WT) mice kept on standard or iron-rich diets. Twelve-month-old hepcidin KO mice were subjected to daily minihepcidin PR73 treatment for 1 week. Six-month-old hepcidin KO mice showed cytoplasmic acinar iron overload and mild pancreatitis, together with elevated expression of the iron uptake mediators DMT1 and Zip14. Acinar atrophy, massive macrophage infiltration, fatty changes and pancreas fibrosis were noted in 1-year-old hepcidin KO mice. As an underlying mechanism, 6-month-old hepcidin KO mice showed increased pancreatic oxidative stress, with elevated DNA damage, apoptosis and activated nuclear factor-κB (NF-κB) signalling. Neither iron overload nor pancreatic damage was observed in WT mice fed iron-rich diet or in Hfe KO mice. Minihepcidin application to hepcidin KO mice led to an improvement in general health status and to iron redistribution from acinar cells to macrophages. It also resulted in decreased NF-κB activation and reduced DNA damage. In conclusion, loss of hepcidin signalling in mice leads to iron overload-induced chronic pancreatitis that is not seen in situations with less severe iron accumulation. The observed tissue injury can be reversed by hepcidin supplementation. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

• MeSH
• Acinar Cells metabolism   MeSH
• Apoptosis physiology   MeSH
• Pancreatitis, Chronic etiology   metabolism   pathology   MeSH
• Cytoplasm metabolism   MeSH
• Hepcidins deficiency   genetics   physiology   MeSH
• Macrophages pathology   MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Oxidative Stress physiology   MeSH
• Pancreas ultrastructure   MeSH
• Iron Overload complications   metabolism   pathology   MeSH
• Microscopy, Electron, Transmission MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH