RelA/p65 promotes osteoclast differentiation by blocking a RANKL-induced apoptotic JNK pathway in mice
Open Access
- 8 May 2008
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 118 (6), 2088-2097
- https://doi.org/10.1172/JCI33392
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-κB 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.Keywords
This publication has 34 references indexed in Scilit:
- RelB is the NF-κB subunit downstream of NIK responsible for osteoclast differentiationProceedings of the National Academy of Sciences of the United States of America, 2008
- Insights into the Structural Basis of the GADD45β-mediated Inactivation of the JNK Kinase, MKK7/JNKK2Journal of Biological Chemistry, 2007
- Osteoclasts: What Do They Do and How Do They Do It?The American Journal of Pathology, 2007
- Integrating cell-signalling pathways with NF-κB and IKK functionNature Reviews Molecular Cell Biology, 2007
- RANKL-stimulated osteoclast-like cell formation in vitro is partially dependent on endogenous interleukin-1 productionBone, 2006
- Map kinase c-Jun N-terminal kinase mediates PMMA induction of osteoclastsJournal of Orthopaedic Research, 2006
- Antioxidant α-lipoic acid inhibits osteoclast differentiation by reducing nuclear factor-κB DNA binding and prevents in vivo bone resorption induced by receptor activator of nuclear factor-κB ligand and tumor necrosis factor-αFree Radical Biology & Medicine, 2006
- Dominant-negative IκB Facilitates Apoptosis of Osteoclasts by Tumor Necrosis Factor-αJournal of Biological Chemistry, 2003
- IAP proteins: blocking the road to death's doorNature Reviews Molecular Cell Biology, 2002
- Requirement for NF-κB in osteoclast and B-cell developmentGenes & Development, 1997