Department of Periodontology, Division of Oral Biology and Disease Control, Osaka University Graduate School of Dentistry, Osaka, Japan.
Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
J Periodontal Res. 2023 Aug;58(4):813-826. doi: 10.1111/jre.13140. Epub 2023 May 23.
BACKGROUND/AIMS: Hyperglycemia in diabetes is closely associated with periodontal disease progression. This study aimed to investigate the effect of hyperglycemia on the barrier function of gingival epithelial cells as a cause of hyperglycemia-exacerbated periodontitis in diabetes mellitus.
The abnormal expression of adhesion molecules in gingival epithelium in diabetes was compared between db/db and control mice. To study the effects of hyperglycemia on interepithelial cell permeability, the mRNA and protein expressions of adhesion molecules were investigated using a human gingival epithelial cell line (epi 4 cells) in the presence of either 5.5 mM glucose (NG) or 30 mM glucose (HG). Immunocytochemical and histological analyses were performed. We also studied HG-related intracellular signaling to assess abnormal adhesion molecule expression in the cultured epi 4 cells.
The results of the proteomic analysis implied the abnormal regulation of cell-cell adhesion, and mRNA and protein expression assessments revealed the significant downregulation of Claudin1 expression in the gingival tissues of db/db mice (p < .05 vs control). Similarly, the mRNA and protein expressions of adhesion molecules were lower in epi 4 cells cultured under HG conditions than in those cultured under NG conditions (p < .05). Three-dimensional culture and transmission electron microscopy revealed reduced thickness of the epithelial cell layers with no flattened apical cells and heterogeneously arranged intercellular spaces among adjacent epi 4 cells under the HG. These results were consistent with the increased permeability of epi 4 cells under the HG relative to that of cells under the NG. This abnormal expression of intercellular adhesion molecules under the HG was related to the increased expression of receptors for advanced glycation end products (AGEs) and oxidative stress relative to that seen under the NG, along with stimulation of ERK1/2 phosphorylation in epi 4 cells.
High glucose-induced impairment of intercellular adhesion molecule expression in gingival epithelial cells was related to the intercellular permeability of gingival cells, representing a possible link to hyperglycemia-related AGE signaling, oxidative stress, and ERK1/2 activation.
背景/目的：糖尿病患者的高血糖与牙周病的进展密切相关。本研究旨在探讨高血糖对牙龈上皮细胞屏障功能的影响，这可能是糖尿病患者高血糖加重牙周炎的原因。
比较 db/db 小鼠和对照小鼠糖尿病牙龈上皮异常表达的黏附分子。为了研究高血糖对细胞间通透性的影响，在存在 5.5mmol/L 葡萄糖（NG）或 30mmol/L 葡萄糖（HG）的情况下，用人类牙龈上皮细胞系（epi 4 细胞）研究黏附分子的 mRNA 和蛋白表达。进行免疫细胞化学和组织学分析。我们还研究了 HG 相关的细胞内信号转导，以评估培养的 epi 4 细胞中异常黏附分子的表达。
蛋白质组学分析的结果表明细胞间黏附的异常调节，mRNA 和蛋白表达评估显示 db/db 小鼠牙龈组织 Claudin1 表达显著下调（p<0.05 与对照相比）。同样，HG 条件下培养的 epi 4 细胞中黏附分子的 mRNA 和蛋白表达低于 NG 条件下培养的细胞（p<0.05）。三维培养和透射电子显微镜显示，HG 条件下 epi 4 细胞的上皮细胞层厚度变薄，没有扁平的顶端细胞，相邻 epi 4 细胞之间的细胞间空间排列不均匀。与 NG 相比，HG 下 epi 4 细胞的通透性增加，这与 HG 下细胞间黏附分子的异常表达一致。HG 下细胞间黏附分子的这种异常表达与 NG 下 AGE 受体和氧化应激的表达增加以及 epi 4 细胞中 ERK1/2 磷酸化的刺激有关。
高糖诱导的牙龈上皮细胞间黏附分子表达受损与牙龈细胞的细胞间通透性有关，这可能与高血糖相关的 AGE 信号、氧化应激和 ERK1/2 激活有关。
