title: JNK1 modulates osteoclastogenesis through both c-Jun phosphorylation-dependent and -independent mechanisms.
abstract: Phosphorylation of the N-terminal domain of Jun by the Jun kinases (JNKs) modulates the transcriptional activity of AP-1, a dimeric transcription factor typically composed of c-Jun and c-Fos, the latter being essential for osteoclast differentiation. Using mice lacking JNK1 or JNK2, we demonstrate that JNK1, but not JNK2, is specifically activated by the osteoclast-differentiating factor RANKL. Activation of JNK1, but not JNK2, is required for efficient osteoclastogenesis from bone marrow monocytes (BMMs). JNK1 protects BMMs from RANKL-induced apoptosis during differentiation. In addition, BMMs from mice carrying a mutant of c-Jun phosphorylation sites (JunAA/JunAA), as well as cells lacking either c-Jun or JunD, which is another JNK substrate, revealed that c-Jun phosphorylation and c-Jun itself, but not JunD, are essential for efficient osteoclastogenesis. Moreover, JNK1-dependent c-Jun phosphorylation in response to RANKL is not involved in the anti-apoptotic function of JNK1. Thus, these data provide genetic evidence that JNK1 activation modulates osteoclastogenesis through both c-Jun-phosphorylation-dependent and -independent mechanisms.
authors.affiliation: Research Institute of Molecular Pathology, Dr Bohr-Gasse 7, A-1030 Vienna, Austria.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: David
authors.forename: Kanaga
authors.initials: K
authors.lastname: Sabapathy
authors.forename: Oskar
authors.initials: O
authors.lastname: Hoffmann
authors.forename: Maria H
authors.initials: MH
authors.lastname: Idarraga
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D006023:Glycoproteins / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology*; D009154:Mutation / Q000235:genetics; D023461:Myeloid Progenitor Cells / Q000187:drug effects / Q000201:enzymology*; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology*; D053244:Osteoprotegerin; D010766:Phosphorylation / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000172:deficiency* / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism
chemical_list: D006023:Glycoproteins; D053244:Osteoprotegerin; D016755:Proto-Oncogene Proteins c-jun; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506031:Tnfrsf11b protein, mouse; D018808:Transcription Factor AP-1; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases