title: Lipopolysaccharide supports survival and fusion of preosteoclasts independent of TNF-alpha, IL-1, and RANKL.
abstract: Lipopolysaccharide (LPS), a cell component of Gram-negative bacteria, is a pathogen of inflammatory bone loss. To examine the effects of LPS on the survival and fusion of osteoclasts, mononuclear osteoclasts (preosteoclasts, pOCs) were collected from a mouse co-culture system and cultured in the presence or absence of LPS. Most pOCs died within 24 h in the absence of any stimulus. LPS as well as receptor activator of NF-kappaB ligand (RANKL) supported the survival of pOCs, and induced their fusion to form multinucleated cells (MNCs). Like authentic osteoclasts, MNCs induced by LPS expressed calcitonin receptors, and formed actin rings on culture plates. LPS-induced MNC formation in pOC cultures was observed even in the presence of osteoprotegerin and interleukin (IL)-1-receptor antagonists. MNC formation was also stimulated by LPS in pOC cultures prepared from tumor necrosis factor (TNF)-receptor-I or TNF-receptor-II deficient mice. LPS induced the degradation of IkappaB in pOCs within 20 min. Lactacystin, an inhibitor of NF-kappaB activation, and wortmannin, an inhibitor of phosphatidylinositol-3 kinase, strongly inhibited LPS-induced MNC formation in pOC cultures. LPS induced pit-forming activity of pOCs in the presence of macrophage-colony stimulating factor (M-CSF). These findings suggest that LPS stimulates the survival and fusion of pOCs, independent of RANKL, IL-1 or TNF-alpha action. Activation of NF-kappaB and phosphatidylinositol-3 kinase appeared to be involved in LPS-induced effects on pOCs. These observations suggest that LPS is involved directly in inflammatory bone loss, and also indirectly through the production of LPS-induced host factors such as IL-1 and TNF-alpha.
authors.affiliation: Department of Bioengineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Suda
authors.forename: Je-Tae
authors.initials: JT
authors.lastname: Woo
authors.forename: Masamichi
authors.initials: M
authors.lastname: Takami
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sexton
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nagai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism* / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002459:Cell Fusion; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins / Q000378:metabolism; D003804:Dentin / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015726:Giant Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins; D007375:Interleukin-1 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008297:Male; D008561:Membrane Fusion / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D046988:Proteasome Endopeptidase Complex; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D009097:Multienzyme Complexes; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000081082:Phosphoinositide-3 Kinase Inhibitors; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D016173:Macrophage Colony-Stimulating Factor; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex