title: Oral administration of prostaglandin E(2)-specific receptor 4 antagonist inhibits lipopolysaccharide-induced osteoclastogenesis in rat periodontal tissue.
abstract: 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-α (TNF-α), the receptor activator of nuclear factor-κB 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-α 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Oka
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Miyauchi
authors.forename: Hisako
authors.initials: H
authors.lastname: Furusho
authors.forename: Tatsuji
authors.initials: T
authors.lastname: Nishihara
authors.forename: Takashi
authors.initials: T
authors.lastname: Takata
mesh_terms: D016976:Aggregatibacter actinomycetemcomitans; D016301:Alveolar Bone Loss / Q000139:chemically induced / Q000473:pathology; D000539:Alveolar Process / Q000187:drug effects / Q000473:pathology; D000818:Animals; D001862:Bone Resorption / Q000139:chemically induced / Q000473:pathology; D002452:Cell Count; D018929:Cell Culture Techniques; D002460:Cell Line; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004926:Escherichia coli; D007213:Indomethacin / Q000494:pharmacology; D015850:Interleukin-6 / Q000032:analysis; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects; D051379:Mice; D009281:Naphthalenes / Q000494:pharmacology*; D010006:Osteoblasts / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects*; D053244:Osteoprotegerin / Q000187:drug effects; D010513:Periodontal Ligament / Q000166:cytology / Q000187:drug effects*; D010654:Phenylbutyrates / Q000494:pharmacology*; D053245:RANK Ligand / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects
chemical_list: C487890:4-(4-cyano-2-(2-(4-fluoronaphthalen-1-yl)propionylamino)phenyl)butyric acid; D016861:Cyclooxygenase Inhibitors; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009281:Naphthalenes; D053244:Osteoprotegerin; D010654:Phenylbutyrates; D053245:RANK Ligand; D058309:Receptors, Prostaglandin E, EP4 Subtype; C506032:Tnfrsf11b protein, rat; D014409:Tumor Necrosis Factor-alpha; D007213:Indomethacin