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

Nidhish Francis, Babatunde A. Ayodele, Neil M. O'Brien-Simpson, Walter Birchmeier, Robert N. Pike, Charles N. Pagel, Eleanor J. Mackie

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 (PAR2). PAR2 expressed on oral keratinocytes is activated by proteases released by P. gingivalis, inducing secretion of interleukin 6 (IL-6), and global knockout of PAR2 prevents bone loss and inflammation in a periodontal disease model in mice. To test the hypothesis that PAR2 expressed on gingival keratinocytes is required for periodontal disease pathology, keratinocyte-specific PAR2-null mice were generated using K14-Cre targeted deletion of the PAR2 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:F2rl1wt/wt), but not littermate keratinocyte-specific PAR2-null (K14-Cre:F2rl1fl/fl) mice. Keratinocyte-specific ablation of PAR2 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 PAR2 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.

Original languageEnglish
Article numbere12891
Pages (from-to)1-13
Number of pages13
JournalCellular Microbiology
Volume20
Issue number11
Early online dateJul 2018
DOIs
Publication statusPublished - Nov 2018

Fingerprint

PAR-2 Receptor
Osteitis
Periodontal Diseases
Keratinocytes
Porphyromonas gingivalis
Periodontitis
Bone and Bones
Interleukin-6
Peptide Hydrolases
Alveolar Bone Loss
X-Ray Microtomography
Chronic Periodontitis
Osteoclasts
Interleukin-1
Interferons
Peroxidase
Ligation
Tooth
Up-Regulation
Epithelial Cells

Cite this

Francis, Nidhish ; Ayodele, Babatunde A. ; O'Brien-Simpson, Neil M. ; Birchmeier, Walter ; Pike, Robert N. ; Pagel, Charles N. ; Mackie, Eleanor J. / Keratinocyte-specific ablation of protease-activated receptor 2 prevents gingival inflammation and bone loss in a mouse model of periodontal disease. In: Cellular Microbiology. 2018 ; Vol. 20, No. 11. pp. 1-13.
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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 (PAR2). PAR2 expressed on oral keratinocytes is activated by proteases released by P. gingivalis, inducing secretion of interleukin 6 (IL-6), and global knockout of PAR2 prevents bone loss and inflammation in a periodontal disease model in mice. To test the hypothesis that PAR2 expressed on gingival keratinocytes is required for periodontal disease pathology, keratinocyte-specific PAR2-null mice were generated using K14-Cre targeted deletion of the PAR2 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:F2rl1wt/wt), but not littermate keratinocyte-specific PAR2-null (K14-Cre:F2rl1fl/fl) mice. Keratinocyte-specific ablation of PAR2 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 PAR2 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.",
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Keratinocyte-specific ablation of protease-activated receptor 2 prevents gingival inflammation and bone loss in a mouse model of periodontal disease. / Francis, Nidhish; Ayodele, Babatunde A.; O'Brien-Simpson, Neil M.; Birchmeier, Walter; Pike, Robert N.; Pagel, Charles N.; Mackie, Eleanor J.

In: Cellular Microbiology, Vol. 20, No. 11, e12891, 11.2018, p. 1-13.

Research output: Contribution to journalArticle

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AU - Francis, Nidhish

AU - Ayodele, Babatunde A.

AU - O'Brien-Simpson, Neil M.

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AU - Mackie, Eleanor J.

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AB - 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 (PAR2). PAR2 expressed on oral keratinocytes is activated by proteases released by P. gingivalis, inducing secretion of interleukin 6 (IL-6), and global knockout of PAR2 prevents bone loss and inflammation in a periodontal disease model in mice. To test the hypothesis that PAR2 expressed on gingival keratinocytes is required for periodontal disease pathology, keratinocyte-specific PAR2-null mice were generated using K14-Cre targeted deletion of the PAR2 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:F2rl1wt/wt), but not littermate keratinocyte-specific PAR2-null (K14-Cre:F2rl1fl/fl) mice. Keratinocyte-specific ablation of PAR2 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 PAR2 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.

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