Extracellular release of a disintegrin and metalloproteinases orchestrates periodontal disease severity

Periodontal diseases are amongst the most common pathologies worldwide with a high risk for the development of systemic complications. Periodontal disease is driven by oral pathogens such as Porphyromonas gingivalis and the release of inflammatory cytokines. These cytokines (e.g. TNF) or their receptors (IL-1R) are substrates of a disintegrin and metalloproteinases (ADAMs). In a comparative approach, we observed an increase of ADAM8 protein expression and activity in the sulcus fluid of periodontal disease patients correlating with the disease stage. In contrast, the induced ADAM10 expression was decreased. In vitro mechanistic studies revealed that both Porphyromonas gingivalis infection and the resulting cytokine release orchestrated the release of soluble ADAM8 by keratinocytes and neutrophils as soluble ectodomain and on exosomes, respectively. Furthermore, ADAM8 regulated the release of ADAM10 and MMP9, thereby potentially influencing wound healing and tissue destruction. Thus, the dysregulation of the cell-associated and extracellular ADAM proteolytic activity mainly driven by ADAM8 may be an essential regulatory element in periodontal disease onset and progression. This potential as novel local treatment option should be addressed in future translational studies.