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Membrane-Bound Prostaglandin E Synthase-1-Mediated Prostaglandin E₂ Production by Osteoblast Plays a Critical Role in Lipopolysaccharide-Induced Bone Loss Associated with Inflammation

Masaki Inada^*, Chiho Matsumoto^*, Satoshi Uematsu, Shizuo Akira and Chisato Miyaura^1,*

^* Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, Tokyo, Japan; and Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

PGE₂ acts as a potent stimulator of bone resorption in several disorders including osteoarthritis and periodontitis. Three PGE synthases (PGES) were isolated for PGE₂ production, but which PGES has the major role in inflammatory bone resorption is still unclear. In this study, we examined the role of PGE₂ in LPS-induced bone resorption using membrane-bound PGES (mPGES)-1-deficient mice (mPges1^–/–). In osteoblasts from wild-type mice, PGE₂ production was greatly stimulated by LPS following the expression of cyclooxygenase 2 and mPGES-1 mRNA, whereas no PGE₂ production was found in osteoblasts from mPges1^–/–. LPS administration reduced the bone volume in wild-type femur that was associated with an increased number of osteoclasts. In mPges1^–/–, however, LPS-induced bone loss was reduced. We next examined whether mPGES-1 deficiency could alter the alveolar bone loss in LPS-induced experimental periodontitis. LPS was injected into the lower gingiva and bone mineral density of alveolar bone was measured. LPS induced the loss of alveolar bone in wild-type, but not in mPges1^–/– mice, suggesting an mPGES-1 deficiency resistant to LPS-induced periodontal bone resorption. To understand the pathway of LPS-induced PGE₂ production in osteoblast, we used C3H/HeJ mice with mutated tlr4. Osteoblasts from C3H/HeJ mice did not respond to LPS, and PGE₂ production was not altered at all. LPS-induced bone loss in the femur was also impaired in C3H/HeJ mice. Thus, LPS binds to TLR4 on osteoblasts that directly induce mPGES-1 expression for PGE₂ synthesis, leading to subsequent bone resorption. Therefore, mPGES-1 may provide a new target for the treatment of inflammatory bone disease.

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