Epidermal growth factor receptor signaling suppresses αvβ6 integrin and promotes periodontal inflammation and bone loss

Abstract

In periodontal disease (PD), bacterial biofilms cause gingival inflammation leading to bone loss. In health, αvβ6 integrin in junctional epithelium maintains anti-inflammatory transforming growth factor-β1 (TGF-β1) signaling, whereas its expression is lost in PD. Bacterial biofilms suppress β6 integrin expression in cultured gingival epithelial cells (GECs) by attenuating TGF-β1 signaling, leading to enhanced pro-inflammatory response. In the present study, we show that GEC exposure to biofilm induced activation of mitogen-activated protein kinases and epidermal growth factor receptor (EGFR). Inhibition of EGFR and ERK stunted both the biofilm-induced ITGB6 suppression and IL1B stimulation. Furthermore, biofilm induced the expression of endogenous EGFR ligands that suppressed ITGB6 and stimulated IL1B expression, indicating that the biofilm effects were mediated by autocrine EGFR signaling. Biofilm and EGFR ligands induced inhibitory phosphorylation of TGF-β1 signaling mediator Smad3 at S208. Overexpression of a phosphorylation-defective mutant of Smad3 (S208A) blunted the β6 integrin suppression. Furthermore, inhibition of EGFR signaling significantly reduced bone loss and inflammation in an experimental PD model. Thus, EGFR inhibition may provide a target for clinical therapies to prevent inflammation and bone loss in PD.