Nguyen T N, Ribes S, Andrique C, Requin M, Bouchet J, Obtel N, Slimani L, Brouilly N, Torrens C, Schmitt A, Guilbert T, Morawietz M, Kiesow A, Brunelle A, Percot A, Hadj-Rabia S, Gaucher C, Le Bivic A, Houillier P, Bardet C, Muller D, Ramirez Rozzi F, Coradin T, Breiderhoff T, Chaussain C
Université Paris Cité, INSERM U1333 Santé Orale, et Plateforme Imagerie du Vivant (PIV), FHU-DDS-net, IHMOA, Dental School, Montrouge, France.
Aix Marseille Université, CNRS, IBDM-UMR7288, Marseille, France.
J Dent Res. 2025 Jul 27:220345251349109. doi: 10.1177/00220345251349109.
Rare disorders related to tight junction (TJ) proteins have been associated with amelogenesis imperfecta. Pathogenic variants of , encoding claudin-10b, a cation transport pore, cause the autosomal recessive HELIX syndrome (Hypohidrosis, Electrolyte imbalance, hypoLacrymia, Ichthyosis, Xerostomia). Patients exhibit salivary dysfunction and rapid enamel wear after tooth eruption. Since C is expressed in the dental epithelium, this study explores the role of claudin-10b in amelogenesis. We analyzed amelogenesis in constitutive and conditional knockout (KO) murine models, comparing the findings to human HELIX enamel. First, analysis of constitutive knockout (KO) mice, which die within a few hours after birth, showed that claudin-10 is present at the plasma membrane of the stratum intermedium but not at the TJs during the secretory stage. Its absence altered gene expression related to ion transport and pH control, although without major disturbance in cell polarization or enamel matrix synthesis. Examination of later stages of amelogenesis in epithelium-targeted conditional KO mice showed that claudin-10 is present in the papillary layer at the maturation stage. In its absence, the pH of the enamel matrix was more basic during early maturation, suggesting that claudin-10 determines enamel matrix pH. However, at later stage of the maturation process, the pH was corrected and the resulting enamel did not show major structural or elemental alterations. These later findings were confirmed by exploring the enamel of KO transplanted tooth germs, which have developed in a controlled mineral environment. Nevertheless, higher contents of aluminum were detected in the enamel of transplanted germs and in human HELIX enamel, suggesting that claudin-10 deficiency may lead to a loss of enamel organ integrity. These data suggest that while salivary dysfunction is the main cause of enamel wear in HELIX, claudin-10 plays a direct role in amelogenesis by determining pH and enamel organ integrity.
与紧密连接（TJ）蛋白相关的罕见疾病与牙釉质发育不全有关。编码紧密连接蛋白10b（一种阳离子转运孔）的基因的致病性变异会导致常染色体隐性遗传的HELIX综合征（少汗、电解质失衡、泪液分泌减少、鱼鳞病、口腔干燥）。患者在牙齿萌出后表现出唾液功能障碍和牙釉质快速磨损。由于紧密连接蛋白10b在牙上皮中表达，本研究探讨了紧密连接蛋白10b在牙釉质形成中的作用。我们在组成型和条件性基因敲除（KO）小鼠模型中分析了牙釉质形成过程，并将结果与人类HELIX综合征的牙釉质进行比较。首先，对出生后数小时内死亡的组成型基因敲除小鼠的分析表明，在分泌期，紧密连接蛋白10存在于中间层的质膜上，但不存在于紧密连接处。其缺失改变了与离子转运和pH控制相关的基因表达，尽管在细胞极化或牙釉质基质合成方面没有受到重大干扰。对上皮靶向性条件性基因敲除小鼠牙釉质形成后期的检查表明，在成熟阶段，紧密连接蛋白10存在于乳头层。在其缺失的情况下，牙釉质基质在成熟早期的pH值更偏碱性，这表明紧密连接蛋白10决定了牙釉质基质的pH值。然而，在成熟过程的后期，pH值得到了纠正，最终形成的牙釉质在结构或元素组成上没有表现出重大改变。通过对在可控矿物质环境中发育的基因敲除移植牙胚的牙釉质进行研究，证实了这些后期发现。尽管如此，在移植牙胚的牙釉质和人类HELIX综合征的牙釉质中检测到了较高含量的铝，这表明紧密连接蛋白10缺乏可能导致牙釉质器官完整性的丧失。这些数据表明，虽然唾液功能障碍是HELIX综合征中牙釉质磨损的主要原因，但紧密连接蛋白10通过决定pH值和牙釉质器官完整性在牙釉质形成中发挥直接作用。
