Interaction between the Wnt/β-catenin signaling pathway and the EMMPRIN/MMP-2, 9 route in periodontitis

In periodontitis, the Wnt/β-catenin signaling pathway is related to the metabolism of the alveolar bone; further, extracellular matrix metalloproteinase inducer (EMMPRIN) expression is correlated with matrix metalloproteinases (MMPs) expression and inflammation severity. The aim of this study was to perform a preliminary investigation of the interaction between the Wnt/β-catenin signaling pathway and the EMMPRIN/MMPs route in periodontitis.

Chronic periodontitis and healthy gingival tissues were obtained to detect the expression of Wnt3a, β-catenin, EMMPRIN and MMP-2, 9 by using immunohistochemical analysis. The human immortalized oral epithelial cell/human gingival fibroblast direct co-culture model was treated with 10 μg/mL Porphyromonas gingivalis lipopolysaccharide (Pg. LPS). Anti-EMMPRIN antibody was used to block the effect of EMMPRIN. Dickkopf-1 (DKK-1) and Wnt3a were used as the inhibitor and activator of the Wnt/β-catenin signaling pathway, respectively. Immunofluorescence was performed to visualize the localization of β-catenin and EMMPRIN. Expression of the EMMPRIN, MMP-2, 9 and Wnt pathway's components was confirmed by western blotting and quantitative real-time polymerase chain reaction.

Higher levels of Wnt3a, β-catenin, EMMPRIN and MMP-2, 9 were observed in chronic periodontitis gingival tissues compared with controls. Pg. LPS significantly enhanced β-catenin, p-GSK-3β, EMMPRIN and MMP-2, 9 inductions in the human immortalized oral epithelial cell/human gingival fibroblast co-culture model. Anti-EMMPRIN antibody markedly reduced the expression of MMP-2, 9 only in the presence of Pg. LPS. Co-expression of β-catenin and EMMPRIN was detected in the co-culture model. DKK-1 inhibited Wnt pathway, but upregulated the EMMPRIN/MMP-2, 9 routes. In contrast, activating Wnt pathway by Wnt3a repressed the EMMPRIN/MMP-2, 9 routes. The promotion effect of DKK-1 on MMP-2, 9 expressions was partially inhibited by the anti-EMMPRIN antibody. In addition, anti-EMMPRIN antibody led to a drastic decrease in β-catenin and p-GSK-3β.

In periodontitis, EMMPRIN regulates MMP-2, 9 expressions, the activation of Wnt/β-catenin signaling pathway downregulates the EMMPRIN/MMP-2, 9 routes and the blockade of EMMPRIN attenuates Wnt/β-catenin signaling pathway.