The Role of Proteinase-Activated Receptors 1 and 2 in the Regulation of Periodontal Tissue Metabolism and Disease

Table 4

In vitro studies on PAR₁ and PAR₂ activation associated with periodontal tissue metabolism.

Author(s)/year	In vivo model	PAR	Experimental groups	Biological effect(s)	Mechanism(s) involved
Holzhausen et al. [65]	Male Wistar rats subjected to ligature-induced periodontitis (right mandibular first molar)	PAR2	(i) Ligature + saline,; (ii) Ligature + SLIGRL-NH2; (agonist peptide),; (iii) Ligature + LRGILS-NH2; (control peptide),; (iv) Sham + saline,; (v) Sham + SLIGRL-NH2,; (vi) Sham + LRGILS-NH2,; Sacrifice at 3, 7, 15, and 30 days	PAR2 agonist induced alveolar bone loss and granulocyte infiltration and exacerbated ligature-induced periodontitis.	Upregulation of COX-1, COX-2, MMP-2, and MMP-9.
Holzhausen et al. [6]	PAR2-deficient mice subjected to P. gingivalis oral infection	PAR2	(i) PAR2^−/− mice + P. gingivalis; oral infection,; (ii) PAR2 WT mice + P. gingivalis,; Sacrifice at 42 and 60 days	PAR2^−/− mice showed less alveolar bone loss compared to WT mice.	PAR2 activation in the presence of P. gingivalis infection increased inflammatory cell infiltration, prostaglandin-E2, IFN-γ, IL-6, and IL-1β levels.
Wong et al. [53]	PAR2-deficient mice subjected to P. gingivalis oral infection	PAR2	(i) PAR2^−/− mice + P. gingivalis; oral infection,; (ii) PAR2 WT mice + P. gingivalis,; Sacrifice at 30 days	PAR2^−/− mice showed less exposed root surface and less alveolar bone eroded surface compared to WT mice.	PAR2-deficient mice showed decreased infiltration of mast cells in the periodontal tissues and impaired T-cell immune responses (decreased activation and Th1/inflammatory response).
	PAR1-deficient mice subjected to P. gingivalis oral infection	PAR1	(i) PAR1^−/− mice + P. gingivalis; oral infection,; (ii) PAR1 WT mice + P. gingivalis,; Sacrifice at 30 days	No difference between PAR1^−/− and PAR1 WT mice with regard to the exposed root surface.
Holzhausen et al. [46]	Male Wistar rats subjected to ligature-induced periodontitis (right mandibular first molar)	PAR2	(i) Control group: daily i.p.; administration of saline,; (ii) Ligature group: ligature; placement and daily i.p.; administration of saline,; (iii) Nafamostat mesilate (NM) group: NM (0.1 mg/kg/day, i.p.) a potent; tryptase inhibitor,; (iv) NM + ligature group: ligature and; daily i.p. NM (0.1 mg/kg/day),; Sacrifice at 7 and 14 days	Tryptase inhibition decreased alveolar bone loss, MPO, and total proteolytic activity in animals subjected to ligature-induced periodontitis.	Tryptase inhibition led to a 1.6-fold decrease in gingival PAR2 expression.
Spolidorio et al. [54]	Male Wistar rats subjected to ligature-induced periodontitis (upper second molars)	PAR1	(i) Ligature + intraoral 3 μg parstatin,; (ii) Ligature + intraoral PBS,; (iii) Sham,; Sacrifice at 8 and 15 days	Parstatin (peptide released upon PAR1 activation) prevented periodontal tissue breakdown.	Parstatin suppressed inflammatory cell infiltration and decreased MPO, IL-1β, TNF-α, and IL-6.
Castro et al. [33]	Male Wistar rats subjected to ligature-induced periodontitis (mandibular first molars)	PAR2	(i) No ligature and no treatment,; (ii) Ligature + placebo (0,9%; NaCl solution),; (iii) Ligature + 5 mg subantimicrobial; dose of doxycycline (SDD) by; daily gavage,; Sacrifice at 3 and 15 days	SDD downregulated alveolar bone loss.	Downregulation of PAR2, IL-17, IL-1β, and TNF-α.

PAR: protease-activated receptor; COX: cyclooxygenase; MMP: matrix metalloproteinase; P. gingivalis: Porphyromonas gingivalis; WT: wild-type mice; IL: interleukin; IFN-γ: interferon gamma; MPO: myeloperoxidase; PBS: phosphate-buffered saline; TNF: tumor necrosis factor.