ABSTRACTPeriodontal disease (PD) is a chronic inflammatory and alveolar bone destructive disease triggered by oral biofilm-producing microorganisms, such asAggregatibacter actinomycetemcomitans. The levels of the phospholipid platelet-activating factor (PAF) in the saliva, gingival crevicular fluid, and periodontal tissues are significantly increased during inflammatory conditions, such as PD, but the exact mechanism that links PAF to alveolar bone resorption is not well understood. In the current study, alveolar bone resorption was induced by experimental PD through the oral inoculation ofA. actinomycetemcomitansin wild-type (WT) and PAF receptor knockout (Pafr−/−) mice.In vitroexperiments usingA. actinomycetemcomitanslipopolysaccharide (LPS)-stimulated RAW 264.7 cells treated with a PAF receptor antagonist (UK74505) were also performed. The expression of lyso-PAF acetyltransferase in periodontal tissues was significantly increased 3 h afterA. actinomycetemcomitansLPS injection in mice. WT andPafr−/−mice that were subjected to oral inoculation ofA. actinomycetemcomitanspresented neutrophil accumulation and increased levels of CXCL-1 and tumor necrosis factor alpha (TNF-α) in periodontal tissues. However,Pafr−/−mice presented less alveolar bone loss than WT mice. Thein vitroblockade of the PAF receptor impaired the resorptive activity ofA. actinomycetemcomitansLPS-activated osteoclasts. In conclusion, this study shows for the first time that the blockade of PAF receptor may contribute to the progression of PD triggered byA. actinomycetemcomitansby directly affecting the differentiation and activity of osteoclasts.