title: RelA/p65 promotes osteoclast differentiation by blocking a RANKL-induced apoptotic JNK pathway in mice.
abstract: Osteoclasts (OCs) function to reabsorb bone and are responsible for the bone loss associated with inflammatory arthritis and osteoporosis. OC numbers are elevated in most disorders of accelerated bone destruction, reflecting altered rates of precursor differentiation and apoptosis. Both of these processes are regulated by the JNK family of MAP kinases. In this study, we have demonstrated that the NF-kappaB subunit RelA/p65 inhibits JNK-mediated apoptosis during a critical period of commitment to the OC phenotype in response to the cytokine RANKL. This RelA/p65-mediated arrest of cell death led to enhanced OC differentiation. Hence, Rela-/- OC precursors displayed prolonged JNK activation in response to RANKL, and this was accompanied by an increase in cell death that prevented efficient differentiation. Although complete blockade of JNK activity inhibits osteoclastogenesis, both short-term blockade in RelA-deficient cultures and suppression of the downstream mediator, Bid rescued apoptosis and differentiation. These antiapoptotic effects were RelA specific, as overexpression of RelA, but not RelB, blocked apoptosis and rescued differentiation in Rela-/- precursors. Thus, RelA blocks a RANKL-induced, apoptotic JNK-Bid pathway, thereby promoting OC differentiation. Consistent with this, mice lacking RelA/p65 in the hematopoietic compartment were shown to have a deficient osteoclastogenic response to RANKL and were protected from arthritis-induced osteolysis.
authors.affiliation: Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Sergio
authors.initials: S
authors.lastname: Vaira
authors.forename: Muhammad
authors.initials: M
authors.lastname: Alhawagri
authors.forename: Imani
authors.initials: I
authors.lastname: Anwisye
authors.forename: Hideki
authors.initials: H
authors.lastname: Kitaura
authors.forename: Roberta
authors.initials: R
authors.lastname: Faccio
authors.forename: Deborah Veis
authors.initials: DV
authors.lastname: Novack
mesh_terms: D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation; D005786:Gene Expression Regulation; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010010:Osteoclasts / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000096:biosynthesis* / Q000502:physiology*
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D053245:RANK Ligand; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020169:Caspases