title: The phosphatidylinositol 3-kinase-mediated production of interferon-beta is critical for the lipopolysaccharide inhibition of osteoclastogenesis.
abstract: OBJECTIVE
  This study was performed to define molecular mechanisms underlying lipopolysaccharide (LPS)-induced inhibition of osteoclastogenesis.
  
  
  METHODS
  The LPS-dependent signaling pathways leading to the inhibition of osteoclastogenesis were examined using chemical inhibitors and neutralizing antibodies.
  
  
  RESULTS
  Lipopolysaccharide (LPS) has been shown to induce massive bone loss in vivo by stimulating osteoclast differentiation and activity. However, the direct effect of LPS on osteoclastogenesis in vitro is complex. Based on the context of the differentiation state of precursors, LPS has been shown to either augment or inhibit osteoclast differentiation. When added to receptor activator of NF-kappaB ligand (RANKL)-primed precursors, LPS enhances osteoclast differentiation via the production of TNF-alpha. On the other hand, LPS inhibits osteoclastogenesis from early precursors like bone marrow macrophages by hitherto unknown mechanism. In the present study, we investigated the mechanism by which LPS inhibits osteoclastogenesis. We have identified that the phosphatidylinositol 3-kinase (PI 3-kinase) dependent production of IFN-beta and resultant inhibition of c-Fos expression upon LPS stimulation of bone marrow macrophages are responsible for the LPS-induced inhibition of osteoclastogenesis. Inhibition of PI 3-kinase, neutralization of IFN-beta, and overexpression of c-Fos respectively prevented the LPS-induced inhibition of osteoclast differentiation.
  
  
  CONCLUSIONS
  Our results provide a molecular understanding of the differentiation stage-specific dual effect of LPS on osteoclastogenesis.
authors.affiliation: Department of Cell and Developmental Biology, BK21 Program, and Dental Research Institute, School of Dentistry, Seoul National University, 28 Yeongon-Dong, Chongno-Gu, Seoul, Korea.
authors.forename: Youngkyun
authors.initials: Y
authors.lastname: Lee
authors.forename: Hao
authors.initials: H
authors.lastname: Huang
authors.forename: Hyung Joon
authors.initials: HJ
authors.lastname: Kim
authors.forename: Chul-Kyu
authors.initials: CK
authors.lastname: Park
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Kim
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016899:Interferon-beta / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D016899:Interferon-beta; D019869:Phosphatidylinositol 3-Kinases