title: Adherent endotoxin on orthopedic wear particles stimulates cytokine production and osteoclast differentiation.
abstract: Aseptic loosening of orthopedic implants is thought to be caused primarily by osteoclast differentiation induced by bone resorptive cytokines produced in response to phagocytosis of implant-derived wear particles. This study examined whether adherent endotoxin on the wear particles is responsible for inducing osteoclast differentiation as well as production of interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor a (TNF-alpha). Removal of adherent endotoxin almost completely inhibited the responses to titanium (Ti) particles by both murine marrow cells and human peripheral blood monocytes. In vivo experiments showed that endotoxin removal reduced particle-induced osteolysis by 50-70%. Addition of lipopolysaccharide (LPS) to the "endotoxin-free" particles restored their ability to induce cytokine production and osteoclast differentiation in vitro. Moreover, marrow cells from mice that are hyporesponsive to endotoxin because of mutation of Toll-like receptor 4 induced significantly less cytokine production and osteoclast differentiation in response to Ti particles with adherent endotoxin than did marrow cells from normoresponsive mice. This mutation also resulted in significantly less particle-induced osteolysis in vivo. Taken together, these results show that adherent endotoxin is involved in many of the biological responses induced by orthopedic wear particles and should stimulate development of new approaches designed to reduce the activity of adherent endotoxin in patients with orthopedic implants.
authors.affiliation: Department of Orthopedics, Case Western Reserve University, Cleveland, Ohio 44106-5000, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Bi
authors.forename: J M
authors.initials: JM
authors.lastname: Seabold
authors.forename: S G
authors.initials: SG
authors.lastname: Kaar
authors.forename: A A
authors.initials: AA
authors.lastname: Ragab
authors.forename: V M
authors.initials: VM
authors.lastname: Goldberg
authors.forename: J M
authors.initials: JM
authors.lastname: Anderson
authors.forename: E M
authors.initials: EM
authors.lastname: Greenfield
mesh_terms: D000268:Adhesiveness; D000818:Animals; D001862:Bone Resorption / Q000209:etiology; D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis*; D029721:Drosophila Proteins; D004731:Endotoxins / Q000633:toxicity*; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000633:toxicity; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000502:physiology; D009154:Mutation; D010010:Osteoclasts / Q000166:cytology*; D010014:Osteolysis / Q000209:etiology; D011475:Prosthesis Failure; D011956:Receptors, Cell Surface / Q000235:genetics; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D016207:Cytokines; D029721:Drosophila Proteins; D004731:Endotoxins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors