RelA/p65 promotes osteoclast differentiation by blocking a RANKL-induced apoptotic JNK pathway in mice

• Published in: The Journal of clinical investigation 2008-06, Vol.118 (6), p.2088-2097
• Main Authors: Vaira, Sergio, Alhawagri, Muhammad, Anwisye, Imani, Kitaura, Hideki, Faccio, Roberta, Novack, Deborah Veis
• Format: Article
• Language: English
• Subjects: Ablation; Animals; Apoptosis; Arthritis; BH3 Interacting Domain Death Agonist Protein - metabolism; Biomedical research; Bone marrow; Bone Marrow Cells - metabolism; Care and treatment; Caspases - metabolism; Cell death; Cell Differentiation; Complications and side effects; Cytokines; Gene Expression Regulation; Health aspects; JNK Mitogen-Activated Protein Kinases - metabolism; Kinases; MAP Kinase Kinase 4 - metabolism; Mice; Mice, Transgenic; Models, Biological; Osteoclasts (Biology); Osteoclasts - metabolism; Osteoporosis; Phosphotransferases; Radiation; RANK Ligand - metabolism; Risk factors; Transcription Factor RelA - biosynthesis; Transcription Factor RelA - physiology; Vertebrae
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci33392

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.