Shahid Shifa, Hu Yuanyuan, Mohamed Fatma, Rizzotto Lara, Layana Michelle C, Fleming Daniel T, Papagerakis Petros, Foster Brian L, Simmer James P, Bartlett John D
Division of Biosciences, College of Dentistry, Ohio State University, 305 W, 12th Ave., Columbus, OH 43210, USA.
Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan 1011 North University, Ann Arbor, MI 48190, USA.
Int J Mol Sci. 2024 Dec 7;25(23):13184. doi: 10.3390/ijms252313184.
ADAM10 is a multi-functional proteinase that can cleave approximately 100 different substrates. Previously, it was demonstrated that ADAM10 is expressed by ameloblasts, which are required for enamel formation. The goal of this study was to determine if ADAM10 is necessary for enamel development. Deletion of in mice is embryonically lethal and deletion of from epithelia is perinatally lethal. We therefore deleted from ameloblasts. Ameloblast-specific expression of the Tg(-i)872pap construct was confirmed. These mice were crossed with floxed mice to generate i; mice ( cKO). The cKO mice had discolored teeth with softer than normal enamel. Notably, the cKO enamel density and volume were significantly reduced in both incisors and molars. Moreover, the incisor enamel rod pattern became progressively more disorganized, moving from the DEJ to the outer enamel surface, and this disorganized rod structure created gaps and S-shaped rods. ADAM10 cleaves proteins essential for cell signaling and for enamel formation such as RELT and COL17A1. ADAM10 also cleaves cell-cell contacts such as E- and N-cadherins that may support ameloblast movement necessary for normal rod patterns. This study shows, for the first time, that ADAM10 expressed by ameloblasts is essential for proper enamel formation.
ADAM10是一种多功能蛋白酶，可切割约100种不同的底物。此前已证明，成釉细胞可表达ADAM10，而成釉细胞是牙釉质形成所必需的。本研究的目的是确定ADAM10对牙釉质发育是否必要。在小鼠中敲除 是胚胎致死性的，而在上皮细胞中敲除 是围产期致死性的。因此，我们从成釉细胞中敲除 。证实了Tg(-i)872pap构建体在成釉细胞中的特异性表达。将这些小鼠与 基因条件性敲除小鼠杂交，以产生i; 小鼠（ 条件性敲除小鼠）。 条件性敲除小鼠的牙齿变色，牙釉质比正常的更软。值得注意的是， 条件性敲除小鼠的切牙和磨牙的牙釉质密度和体积均显著降低。此外，切牙的釉柱模式从牙本质釉质界到牙釉质外表面逐渐变得更加紊乱，这种紊乱的柱结构产生了间隙和S形柱。ADAM10可切割细胞信号传导和牙釉质形成所必需的蛋白质，如RELT和COL17A1。ADAM10还可切割细胞间连接，如E-钙黏蛋白和N-钙黏蛋白，这些连接可能支持正常柱模式所需的成釉细胞移动。本研究首次表明，成釉细胞表达的ADAM10对正常牙釉质形成至关重要。
