title: RANKL is an essential cytokine mediator of polymethylmethacrylate particle-induced osteoclastogenesis.
abstract: RANKL is a TNF superfamily member and an essential cytokine mediator of developmental osteoclastogenesis. We examined the role of RANKL in PMMA particle-induced osteoclastogenesis in vitro. In murine whole bone marrow cultures, PMMA particles stimulate a 2.5 fold increase in secreted RANKL, a 5-8 fold increase in osteoclast number and induce the formation of giant multinuclear osteoclasts. RANKL and TNF, potential cytokine mediators of PMMA, had similar osteoclastogenic effects. The RANKL inhibitor OPG was utilized to define the role of RANKL in mediating the PMMA response and was found to inhibit basal and PMMA particle-induced osteoclastogenesis. Additionally, particles stimulate osteoclast formation in RANKL-primed osteoclast precursor cells (devoid of supporting stromal cells) while RANKL untreated osteoclast precursors demonstrate no osteoclastogenic response to particles. Since TNF can potentiate RANKL action and is thought to mediate implant osteolysis we analyzed TNF(-/-) whole bone marrow cultures to elucidate the role of this cytokine. In TNF(-/-) cultures basal osteoclastogenesis remains intact, yet the PMMA effect is blunted. Finally, we show that PMMA, RANKL and TNF all activate the NF-kB and c-jun/AP-1 signaling pathways which are both fundamental to osteoclast formation and are potential sites of signal convergence in RANKL-mediated particle osteoclastogenesis.
authors.affiliation: Department of Orthopaedic Surgery, Barnes-Jewish Hospital at Washington University, School of Medicine, One Barnes-Jewish Hospital Plaza, 11300 West Pavilion, Campus Box 8233, St. Louis, Missouri 63110, USA. jclohisy@msnotes.wustl.edu
authors.forename: John C
authors.initials: JC
authors.lastname: Clohisy
authors.forename: Elfaridah
authors.initials: E
authors.lastname: Frazier
authors.forename: Teruhisa
authors.initials: T
authors.lastname: Hirayama
authors.forename: Yousef
authors.initials: Y
authors.lastname: Abu-Amer
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism*; D002352:Carrier Proteins / Q000494:pharmacology*; D002452:Cell Count; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D015726:Giant Cells; D006023:Glycoproteins / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000096:biosynthesis; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D053244:Osteoprotegerin; D011109:Polymethacrylic Acids / Q000494:pharmacology*; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053244:Osteoprotegerin; D011109:Polymethacrylic Acids; D016755:Proto-Oncogene Proteins c-jun; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C030613:polymethacrylic acid