Prostaglandin E Receptor EP4 Antagonist Suppresses Lipopolysaccharide-Induced Osteoclast Formation and Inflammatory Bone Loss

Abstract

Prostaglandin E₂ (PGE₂) is mainly produced by osteoblasts in bone tissue, and acts as a potent stimulator of bone resorption. In osteoblasts, PGE₂ production was greatly stimulated by lipopolysaccharide (LPS) following the expression of cyclooxygenase (COX)-2 and membrane-bound PGE synthase (mPGES)-1 mRNA. In the coculture of mouse bone marrow cells and osteoblasts, LPS induced PGE production and osteoclast formation, and EP4 antagonist completely suppressed osteoclast formation, indicating that the PGE₂-mediated EP4 signal is essential for LPS-induced osteoclast formation. Inflammatory bone diseases including periodontitis are known to be accompanied by bone loss with increased osteoclastogenesis. To examine the role of EP4-mediated PGE₂ action in periodontitis, we examined the effects of EP4 antagonist on LPS-induced bone resorption using mouse alveolar bone. In an organ culture of alveolar bone, LPS-induced bone resorbing activity and EP4 antagonist suppressed this LPS-induced bone resorption. In an experimental model of periodontitis, LPS was injected into the lower gingiva, and the bone mineral density of alveolar bone was measured. LPS-induced the loss of alveolar bone, which was recovered by the treatment with EP4 antagonist in vivo. Therefore, EP4 antagonist is a possible candidate for the therapy of inflammatory bone disease including periodontitis.