title: NFAT2 is an essential mediator of orthopedic particle-induced osteoclastogenesis.
abstract: Particle-induced periprosthetic osteolysis is the major cause for orthopedic implant failure. This failure is mediated mainly by the action of osteoclasts, the principal cells responsible for bone resorption and osteolysis. Therapeutic interventions to alleviate osteolysis have been focused on understanding and targeting mechanisms of osteoclastogenesis. The nuclear transcription factor NFAT is an essential terminal differentiation factor of osteoclastogenesis. This transcription factor is known to cooperate with c-jun/AP-1 in mediating RANKL-induced osteoclastogenesis. We have previously determined that RANKL is an essential cytokine mediator of particle-induced osteoclastogenesis, and that PMMA particles activate JNK and c-jun/AP-1 in bone marrow macrophages (osteoclast precursors). In the current study, we investigated the effect of PMMA particles on the NFAT signaling pathway in osteoclast precursor cells. Our findings point out that PMMA particles stimulate nuclear translocation of NFAT2 in wild-type osteoclast precursors, which is associated with increased osteoclastogenesis. More importantly, induction of osteoclastogenesis was selectively blocked in a dose-dependent fashion by the calcineurin inhibitors, Cyclosporine-A and FK506. Further, this activation was also blocked in a time-dependent fashion by the NFAT inhibitor VIVIT. Finally, we provide novel evidence that PMMA particles induce binding of NFAT2 and AP-1 proteins. Thus, our findings demonstrate that activation of the NFAT pathway in conjunction with MAP kinases is essential for basal and PMMA-stimulated osteoclastogenesis.
authors.affiliation: Department of Orthopedics, Washington University School of Medicine, One Barnes Hospital Plaza, 11300 West Pavilion, Campus Box 8233, St. Louis, Missouri 63110, USA.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamanaka
authors.forename: Wahid
authors.initials: W
authors.lastname: Abu-Amer
authors.forename: Dominica
authors.initials: D
authors.lastname: Foglia
authors.forename: Jesse
authors.initials: J
authors.lastname: Otero
authors.forename: John C
authors.initials: JC
authors.lastname: Clohisy
authors.forename: Yousef
authors.initials: Y
authors.lastname: Abu-Amer
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects; D010014:Osteolysis / Q000139:chemically induced; D019904:Polymethyl Methacrylate / Q000009:adverse effects / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D007166:Immunosuppressive Agents; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D009842:Oligopeptides; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; C121611:VIVIT peptide; D016572:Cyclosporine; D004247:DNA; D019904:Polymethyl Methacrylate; D016559:Tacrolimus