title: Membrane-bound prostaglandin E synthase-1-mediated prostaglandin E2 production by osteoblast plays a critical role in lipopolysaccharide-induced bone loss associated with inflammation.
abstract: PGE(2) acts as a potent stimulator of bone resorption in several disorders including osteoarthritis and periodontitis. Three PGE synthases (PGES) were isolated for PGE(2) production, but which PGES has the major role in inflammatory bone resorption is still unclear. In this study, we examined the role of PGE(2) in LPS-induced bone resorption using membrane-bound PGES (mPGES)-1-deficient mice (mPges1(-/-)). In osteoblasts from wild-type mice, PGE(2) production was greatly stimulated by LPS following the expression of cyclooxygenase 2 and mPGES-1 mRNA, whereas no PGE(2) 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 PGE(2) production in osteoblast, we used C3H/HeJ mice with mutated tlr4. Osteoblasts from C3H/HeJ mice did not respond to LPS, and PGE(2) 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 PGE(2) synthesis, leading to subsequent bone resorption. Therefore, mPGES-1 may provide a new target for the treatment of inflammatory bone disease.
authors.affiliation: Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, Tokyo, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Inada
authors.forename: Chiho
authors.initials: C
authors.lastname: Matsumoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Chisato
authors.initials: C
authors.lastname: Miyaura
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D001862:Bone Resorption / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D015232:Dinoprostone / Q000096:biosynthesis*; D004195:Disease Models, Animal; D007249:Inflammation / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D010006:Osteoblasts / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D010518:Periodontitis / Q000201:enzymology / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D011485:Protein Binding / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D017154:Stromal Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000502:physiology
chemical_list: D008070:Lipopolysaccharides; D008565:Membrane Proteins; D012333:RNA, Messenger; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone