title: Critical role for αvβ6 integrin in enamel biomineralization.
abstract: Tooth enamel has the highest degree of biomineralization of all vertebrate hard tissues. During the secretory stage of enamel formation, ameloblasts deposit an extracellular matrix that is in direct contact with the ameloblast plasma membrane. Although it is known that integrins mediate cell-matrix adhesion and regulate cell signaling in most cell types, the receptors that regulate ameloblast adhesion and matrix production are not well characterized. We hypothesized that αvβ6 integrin is expressed in ameloblasts where it regulates biomineralization of enamel. Human and mouse ameloblasts were found to express both β6 integrin mRNA and protein. The maxillary incisors of Itgb6(-/-) mice lacked yellow pigment and their mandibular incisors appeared chalky and rounded. Molars of Itgb6(-/-) mice showed signs of reduced mineralization and severe attrition. The mineral-to-protein ratio in the incisors was significantly reduced in Itgb6(-/-) enamel, mimicking hypomineralized amelogenesis imperfecta. Interestingly, amelogenin-rich extracellular matrix abnormally accumulated between the ameloblast layer of Itgb6(-/-) mouse incisors and the forming enamel surface, and also between ameloblasts. This accumulation was related to increased synthesis of amelogenin, rather than to reduced removal of the matrix proteins. This was confirmed in cultured ameloblast-like cells, in which αvβ6 integrin was not an endocytosis receptor for amelogenins, although it participated in cell adhesion on this matrix indirectly via endogenously produced matrix proteins. In summary, integrin αvβ6 is expressed by ameloblasts and it plays a crucial role in regulating amelogenin deposition and/or turnover and subsequent enamel biomineralization.
authors.affiliation: Faculty of Dentistry, Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Leila
authors.initials: L
authors.lastname: Mohazab
authors.forename: Leeni
authors.initials: L
authors.lastname: Koivisto
authors.forename: Guoqiao
authors.initials: G
authors.lastname: Jiang
authors.forename: Leena
authors.initials: L
authors.lastname: Kytömäki
authors.forename: Markus
authors.initials: M
authors.lastname: Haapasalo
authors.forename: Gethin R
authors.initials: GR
authors.lastname: Owen
authors.forename: Colin
authors.initials: C
authors.lastname: Wiebe
authors.forename: Yanshuang
authors.initials: Y
authors.lastname: Xie
authors.forename: Kristiina
authors.initials: K
authors.lastname: Heikinheimo
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yoshida
authors.forename: Charles E
authors.initials: CE
authors.lastname: Smith
authors.forename: Jyrki
authors.initials: J
authors.lastname: Heino
authors.forename: Lari
authors.initials: L
authors.lastname: Häkkinen
authors.forename: Marc D
authors.initials: MD
authors.lastname: McKee
authors.forename: Hannu
authors.initials: H
authors.lastname: Larjava
mesh_terms: D000565:Ameloblasts / Q000378:metabolism* / Q000473:pathology; D000567:Amelogenesis Imperfecta / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D053523:Amelogenin / Q000378:metabolism; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D002478:Cells, Cultured; D003743:Dental Enamel / Q000378:metabolism* / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019217:Tooth Attrition / Q000209:etiology / Q000517:prevention & control*; D014074:Tooth Calcification / Q000235:genetics; D017001:Tooth Demineralization
chemical_list: D053523:Amelogenin; D000951:Antigens, Neoplasm; D016023:Integrins; C073878:integrin alphavbeta6