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Abstract: Periodontitis, an inflammatory disorder of the supporting tissue of teeth, is one of the most common infectious diseases in humans. Periodontal pathogens promote inflammatory cytokines such as interleukin-1 (IL-1) and prostaglandin E2 (PGE2), resulting in alveolar bone destruction. In the present study, we examined the cellular and molecular mechanisms of IL-1-induced osteoclastogenesis using a coculture system of human periodontal ligament (PDL) cells and mouse spleen cells. IL-1α induced tartrate-resistant acid phosphatase positive (TRAP+) cell formation in a dose-dependent manner. IL-1α up-regulated receptor activator of NF-κB ligand (RANKL) and down-regulated osteoprotegerin (OPG) mRNA expression in PDL cells. The addition of cell-permeable PKI, an inhibitor of the cAMP/PKA signaling pathway, to the cocultures 8 h after the IL-1α stimulation inhibited IL-1α-induced TRAP+ cell formation. IL-1α-induced TRAP+ cell formation was completely blocked by either NS398, a selective inhibitor of cyclooxygenase (COX)-2, or PD98059, a specific inhibitor of extracellular signal-regulated kinase (ERK). Pretreatment with NS398 and PD98059 also inhibited both the up-regulation of RANKL and the down-regulation of OPG expression by IL-1α in PDL cells. IL-1α activated ERK phosphorylation and PD98059 greatly inhibited both COX-2 mRNA expression and PGE2 production induced by IL-1α in PDL cells. In contrast, NEMO binding domain (NBD) peptide, a specific inhibitor of NF-κB signaling, did not affect COX2, RANKL, or OPG mRNA expression induced by IL-1α. These results suggest that IL-1α stimulates osteoclast formation by increasing the expression level of RANKL versus OPG via ERK-dependent PGE2 production in PDL cells. [Copyright &y& Elsevier]