title: Map kinase c-JUN N-terminal kinase mediates PMMA induction of osteoclasts.
abstract: Erosive osteolysis induced by implant-derived wear debris is mediated by recruitment and activation of osteoclasts in a pro-inflammatory microenvironment that is enriched with osteoclastogenic and pro-inflammatory cytokines such as RANKL and tumor necrosis factor alpha (TNF-alpha). These cytokines activate the transcription factor NF-kappaB and MAP kinases, including c-Jun, Erks, and p38, all known to be essential for the development of osteoclasts. We have recently documented that TNF and RANKL play a pivotal role in the development of inflammatory osteolysis. We have also found that polymethyl methacrylate (PMMA) particles stimulate osteoclastogenesis, at least in part, by induction of RANKL, TNF, and by activation of NF-kappaB and MAP kinases. More importantly, our data indicate that inhibitors of NF-kappaB and the MAP kinases p38 and ERK abrogate particle-induced osteoclastogenesis. In the current study, we investigated if inhibition of c-Jun N-Terminal kinase (JNK) pathway alters PMMA-induced osteoclastogenesis. Our findings point out that PMMA particles activate the JNK pathway in wild-type and TLR4-null (endotoxin-resistant) osteoclast precursors. This activation was selectively blocked in a dose-dependent fashion by the JNK inhibitor SP600125. Most importantly, we provide evidence that SP600125 inhibits osteoclast formation in a reversible manner. Collectively, our findings demonstrate that activation of the JNK pathway is essential for basal and PMMA-stimulated osteoclastogenesis, and buttress the potential significance of targeting the JNK pathway to inhibit osteolysis.
authors.affiliation: Department of Orthopaedics, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yamanaka
authors.forename: Y
authors.initials: Y
authors.lastname: Abu-Amer
authors.forename: R
authors.initials: R
authors.lastname: Faccio
authors.forename: J C
authors.initials: JC
authors.lastname: Clohisy
mesh_terms: D000818:Animals; D000873:Anthracenes; D019643:Arthroplasty, Replacement / Q000009:adverse effects; D001862:Bone Resorption / Q000209:etiology*; D004247:DNA / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects*; D008070:Lipopolysaccharides; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D010010:Osteoclasts / Q000187:drug effects*; D010766:Phosphorylation; D019904:Polymethyl Methacrylate / Q000009:adverse effects*; D051197:Toll-Like Receptor 4 / Q000235:genetics; D018808:Transcription Factor AP-1
chemical_list: D000873:Anthracenes; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D018808:Transcription Factor AP-1; C432165:pyrazolanthrone; D004247:DNA; D019904:Polymethyl Methacrylate; D048031:JNK Mitogen-Activated Protein Kinases