Keratinocyte-specific ablation of protease-activated receptor-2 prevents gingival inflammation and bone loss in a mouse model of periodontal disease.

Chronic periodontitis is characterised by gingival inflammation and alveolar bone loss. A major aetiological agent is Porphyromonas gingivalis, which secretes proteases that activate protease-activated receptor 2 (PAR(2)). PAR(2) expressed on oral keratinocytes is activated by proteases released by P. gingivalis, inducing secretion of interleukin 6 (IL-6), and global knockout of PAR(2) prevents bone loss and inflammation in a periodontal disease model in mice. To test the hypothesis that PAR(2) expressed on gingival keratinocytes is required for periodontal disease pathology, keratinocyte-specific PAR(2)-null mice were generated using K14-Cre targeted deletion of the PAR(2) gene (F2rl1). These mice were subjected to a model of periodontitis involving placement of a ligature around a tooth, combined with P. gingivalis infection ("Lig+Inf"). The intervention caused a significant 44% decrease in alveolar bone volume (assessed by microcomputed tomography) in wildtype (K14-Cre:F2rl1(wt/wt)), but not littermate keratinocyte-specific PAR(2)-null (K14-Cre:F2rl1(fl/fl)) mice. Keratinocyte-specific ablation of PAR(2) prevented the significant Lig + Inf-induced increase (2.8-fold) in the number of osteoclasts in alveolar bone and the significant up-regulation (2.4-4-fold) of the inflammatory markers IL-6, IL-1 beta, interferon-gamma, myeloperoxidase, and CD11b in gingival tissue. These data suggest that PAR(2) expressed on oral epithelial cells is a critical regulator of periodontitis-induced bone loss and will help in designing novel therapies with which to treat the disease.