AimPeriodontal disease is driven by oral pathogens, including Porphyromonas gingivalis, and the release of inflammatory cytokines. These cytokines (e.g., TNF) or their receptors (e.g., IL‐1R) are substrates of a disintegrin and metalloproteinases (ADAMs). In this study, we aimed to determine the effects of ADAMs on periodontal disease phenotypes.Materials and MethodsWestern blot and FRET‐based activity measurements of the gingival crevicular fluid (GCF) of patients were compared with those of infected (P. gingivalis) or cytokine‐stimulated oral keratinocytes and primary human neutrophils, respectively. This was accompanied by an analysis of the released extracellular vesicles and MMP9 activity.ResultsIn the GCF of patients, ADAM8 protein expression and activity were correlated with disease stage, whereas ADAM10 protein expression was inversely correlated with disease stage. Infection and the resulting cytokine release orchestrated the release of soluble ADAM8 by oral keratinocytes and primary neutrophils as soluble ectodomain and on exosomes, respectively. Furthermore, ADAM8 regulated the release of ADAM10 and MMP9.ConclusionDysregulation of cell‐associated and extracellular ADAM proteolytic activity may be an essential regulatory element in the progression of periodontal disease driven by ADAM8. The influence of ADAM8 on disease onset and the evaluation of targeting ADAM8 as a potential and novel local treatment option should be addressed in future translational in vivo studies.

中文翻译：

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解整合素和金属蛋白酶的细胞外释放与牙周病严重程度相关


目的牙周病是由口腔病原体（包括牙龈卟啉单胞菌）和炎症细胞因子的释放引起的。这些细胞因子（例如 TNF）或其受体（例如 IL-1R）是解整合素和金属蛋白酶 (ADAM) 的底物。在本研究中，我们旨在确定 ADAM 对牙周病表型的影响。 材料和方法将患者龈沟液 (GCF) 的蛋白质印迹和基于 FRET 的活性测量与感染者（牙龈卟啉单胞菌）或细胞因子的进行比较‐分别刺激口腔角质形成细胞和原代人中性粒细胞。同时对释放的细胞外囊泡和 MMP9 活性进行分析。结果在患者的 GCF 中，ADAM8 蛋白表达和活性与疾病阶段相关，而 ADAM10 蛋白表达与疾病阶段呈负相关。感染和由此产生的细胞因子释放协调了口腔角质形成细胞和原代中性粒细胞分别作为可溶性胞外域和外泌体释放可溶性 ADAM8。此外，ADAM8还调节ADAM10和MMP9的释放。结论细胞相关和细胞外ADAM蛋白水解活性的失调可能是ADAM8驱动的牙周病进展的重要调节因素。 ADAM8 对疾病发作的影响以及将 ADAM8 作为潜在的新型局部治疗选择的评估应在未来的体内转化研究中解决。