title: Tumor necrosis factor-alpha mediates polymethylmethacrylate particle-induced NF-kappaB activation in osteoclast precursor cells.
abstract: Tumor necrosis factor-alpha (TNF) is a potent osteoclastogenic cytokine that has a fundamental role in the pathogenesis of implant particle-induced osteolysis. The nuclear transcription factor NF-kappaB mediates TNF signaling and this transcription complex is necessary for osteoclastogenesis. Because polymethylmethacrylate (PMMA) particles cause osteolysis, we reasoned the PMMA would induce NF-kappaB activation. In fact, we find that exposure of osteoclast precursors, in the form of colony stimulating factor-1 (CSF-1) dependent murine bone marrow macrophages, to PMMA particles prompts nuclear translocation and activation of NF-kappaB. Supershift assays confirm the presence of the p50 and p65 NF-kappaB subunits in the activated transcription factor. Particle-induced NF-kappaB activation is equal in both wild type and LPS- hyporesponsive cells indicating that the phenomenon does not represent endotoxin contamination. A soluble, competitive inhibitor of TNF (huTNFr:Fc) dampens particle-directed NF-kappaB activation and this response is also abrogated in TNF-/- osteoclast precursors. Thus, PMMA particle activation of NF-kappaB is a secondary event resulting from enhanced TNF expression and is independent of LPS contamination.
authors.affiliation: Department of Orthopaedic Surgery, Barnes-Jewish Hospital at Washington University School of Medicine, St. Louis, MO 63110, USA. jclohisy@msnotes.wustl.edu
authors.forename: John C
authors.initials: JC
authors.lastname: Clohisy
authors.forename: Steven
authors.initials: S
authors.lastname: Teitelbaum
authors.forename: Shaoping
authors.initials: S
authors.lastname: Chen
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Erdmann
authors.forename: Yousef
authors.initials: Y
authors.lastname: Abu-Amer
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D016328:NF-kappa B / Q000096:biosynthesis*; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D010014:Osteolysis / Q000209:etiology*; D010316:Particle Size; D019904:Polymethyl Methacrylate / Q000494:pharmacology*; D011475:Prosthesis Failure; D011994:Recombinant Proteins / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019904:Polymethyl Methacrylate