Department of Orofacial Sciences, School of Dentistry, University of California San Francisco, San Francisco, USA.
Division of Anatomy and Cell Biology of the Hard Tissue, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Biol Trace Elem Res. 2021 Aug;199(8):3021-3034. doi: 10.1007/s12011-020-02434-y. Epub 2020 Oct 28.
Fluoride can alter the formation of mineralized tissues, including enamel, dentin, and bone. Dentin fluorosis occurs in tandem with enamel fluorosis. However, the pathogenesis of dentin fluorosis and its mechanisms are poorly understood. In this study, we report the effects of fluoride on the initiation of dentin matrix formation and odontoblast function. Mice from two enamel fluorosis susceptible strains (A/J and C57BL/6J) were given either 0 or 50 ppm fluoride in drinking water for 4 weeks. In both mouse strains, there was no overall change in dentin thickness, but fluoride treatment resulted in a significant increase in the thickness of the predentin layer. The lightly mineralized layer (LL), which lies at the border between predentin and fully mineralized dentin and is associated with dentin phosphoprotein (DPP), was absent in fluoride exposed mice. Consistent with a possible reduction of DPP, fluoride-treated mice showed reduced immunostaining for dentin sialoprotein (DSP). Fluoride reduced RUNX2, the transcription regulator of dentin sialophosphoprotein (DSPP), that is cleaved to form both DPP and DSP. In fluoride-treated mouse odontoblasts, the effect of fluoride was further seen in the upstream of RUNX2 as the reduced nuclear translocation of β-catenin and phosphorylated p65/NFκB. In vitro, MD10-F2 pre-odontoblast cells showed inhibition of the Dspp mRNA level in the presence of 10 μM fluoride, and qPCR analysis showed a significantly downregulated level of mRNAs for RUNX2, β-catenin, and Wnt10b. These findings indicate that in mice, systemic exposure to excess fluoride resulted in reduced Wnt/β-catenin signaling in differentiating odontoblasts to downregulate DSPP production via RUNX2.
氟化物会改变矿化组织的形成，包括牙釉质、牙本质和骨。牙本质氟中毒与釉质氟中毒同时发生。然而，牙本质氟中毒的发病机制及其机制仍知之甚少。在这项研究中，我们报告了氟化物对牙本质基质形成和成牙本质细胞功能的影响。来自两个釉质氟中毒易感品系（A/J 和 C57BL/6J）的小鼠分别用 0 或 50ppm 的氟化物饮用水处理 4 周。在这两种小鼠品系中，牙本质厚度均无总体变化，但氟化物处理导致前期牙本质层厚度显著增加。轻度矿化层（LL）位于前期牙本质和完全矿化牙本质之间的边界处，与牙本质磷蛋白（DPP）有关，在氟化物暴露的小鼠中不存在。与可能减少 DPP 一致，氟化物处理的小鼠显示出牙本质涎磷蛋白（DSP）的免疫染色减少。氟化物降低了 RUNX2，牙本质涎磷蛋白（DSPP）的转录调节因子，该蛋白被切割形成 DPP 和 DSP。在氟化物处理的小鼠成牙本质细胞中，RUNX2 的上游也观察到了氟化物的作用，β-连环蛋白和磷酸化 p65/NFκB 的核易位减少。在体外，MD10-F2 前成牙本质细胞在存在 10μM 氟化物的情况下显示 Dspp mRNA 水平受到抑制，qPCR 分析显示 RUNX2、β-连环蛋白和 Wnt10b 的 mRNA 水平显著下调。这些发现表明，在小鼠中，全身暴露于过量氟化物会导致分化中的成牙本质细胞中 Wnt/β-连环蛋白信号降低，通过 RUNX2 下调 DSPP 产生。
