title: Blockade of JNK and NFAT pathways attenuates orthopedic particle-stimulated osteoclastogenesis of human osteoclast precursors and murine calvarial osteolysis.
abstract: Particles released from orthopedic implants attract immune host defense cells to the bone-implant interface and contribute to development of inflammation. The inflammatory microenvironment supports recruitment and differentiation of osteoclasts, the primary culprit of osteolysis. Therefore, understanding the complex signals that contribute to osteoclastogenesis and osteolysis is a sensible approach to design strategies to inhibit bone loss. The signaling cascades that coordinate osteoclastogenesis have been widely investigated. These include MAP kinases, Akt/PI3K pathway, NF-κB signal transduction pathway, and NFAT pathway. We have recently reported that polymethylmethacrylate (PMMA) particles activate the NFAT pathway in murine osteoclast precursors and that NFAT inhibitors dose-dependently block PMMA-induced osteoclastogenesis. In the current study, we examined the role of JNK and NFATc1 in mice in response to PMMA particles using murine calvaria model. We show that locally administered MAPK/JNK inhibitor SP600125 and calcineurin/NFAT inhibitor cyclosporine-A effectively blocked PMMA-induced osteolysis in murine calvaria. To buttress the clinical relevance of JNK/NFATc1-based regulation of PMMA-induced osteoclastogenesis, we evaluated the effect of PMMA using human macrophages. We demonstrate that SP600125 and cyclosporine-A abolished particle-induced osteoclastogenesis in human osteoclast progenitors retrieved from patients undergoing total hip replacement. Thus JNK and NFATc1 appear to act as significant mediators of orthopedic particle-induced osteolysis in humans.
authors: Department of Orthopedics, Asahikawa Medical University, Asahikawa, Japan.
authors: Yasuhiro
authors: Y
authors: Yamanaka
authors: John C F
authors: JC
authors: Clohisy
authors: Hiroshi
authors: H
authors: Ito
authors: Takeo
authors: T
authors: Matsuno
authors: Yousef
authors: Y
authors: Abu-Amer
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001843:Bone Cements / Q000737:chemistry / Q000633:toxicity; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010014:Osteolysis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D010316:Particle Size; D019904:Polymethyl Methacrylate / Q000737:chemistry / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D012886:Skull / Q000166:cytology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000873:Anthracenes; D001843:Bone Cements; D004791:Enzyme Inhibitors; D050778:NFATC Transcription Factors; C432165:pyrazolanthrone; D016572:Cyclosporine; D019904:Polymethyl Methacrylate; D048031:JNK Mitogen-Activated Protein Kinases