Oral Administration of Prostaglandin E2-Specific Receptor 4 Antagonist Inhibits Lipopolysaccharide-Induced Osteoclastogenesis in Rat Periodontal Tissue

Background: Lipopolysaccharide (LPS) from periodontal pathogens is one of the main causes of alveolar bone destruction. Prostaglandin E-2 (PGE(2)) produced by host cells after LPS stimulation may contribute to the bone destruction. PGE(2) regulates osteoblast-mediated osteoclastogenesis via PGE-specific receptor 4 (EP4). We examined the effects of the PGE(2)-EP4 pathway on the expression of osteoclastogenesis-related factors and studied the inhibitory effect of orally administered EP4-specific antagonist (EP4A) on LPS-induced bone destruction compared to complete inhibition of endogenous PGE(2) by indomethacin (IND). Methods: ST2 cells were treated with IND or EP4A and stimulated by LPS. The mRNA expressions of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), the receptor activator of nuclear factor-kappa B ligand (RANKL), and osteoprotegerin in ST2 cells were examined by quantitative reverse transcription-polymerase chain reaction. LPS-induced bone destruction was examined using a rat model for the periodontal tissue destruction with topically applied LPS. Results: IND and EP4A inhibited the upregulation of TNF-alpha mRNA expression, and only EP4A inhibited IL-6 and RANKL mRNA expressions in ST2 cells with LPS stimulation. Topically applied LPS induced a two-phase increase in osteoclasts along the alveolar bone margin, peaking after 3 hours and 3 days. Oral administration of EP4A and IND downregulated the later phase increase of osteoclasts. However, the early phase of increase at 3 hours was upregulated in IND-treated rats but not in EP4A-treated rats. Conclusion: It appears that the PGE(2)-EP4 pathway has an important role in LPS-induced osteoclastogenesis, and the specific blocking of the PGE(2)-EP4 pathway by EP4A can effectively downregulate bone destruction caused by LPS without an unexpected increased number of osteoclasts. J Periodontol 2012;83:506-513.