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

Item Type:	Article
Title:	Keratinocyte-specific ablation of protease-activated receptor-2 prevents gingival inflammation and bone loss in a mouse model of periodontal disease
Creators Name:	Francis, N. and Ayodele, B.A. and O'Brien-Simpson, N.M. and Birchmeier, W. and Pike, R.N. and Pagel, C.N. and Mackie, E.J.
Abstract:	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 micro‐computed 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‐1β, interferon‐γ, 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.
Keywords:	Alveolar Bone Loss, Animal Disease Models, Bacteroidaceae Infections, CD11b Antigen, Gene Expression Regulation, Gingivitis, Interleukin-6, Keratinocytes, Mutant Strains Mice, PAR-2 Receptor, Periodontal Diseases, Porphyromonas gingivalis, Animals, Mice
Source:	Cellular Microbiology
ISSN:	1462-5814
Publisher:	Wiley-Blackwell
Volume:	20
Number:	11
Page Range:	e12891
Date:	November 2018
Official Publication:	https://doi.org/10.1111/cmi.12891
PubMed:	View item in PubMed

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