RelA/p65 promotes osteoclast differentiation by blocking a RANKL-induced apoptotic JNK pathway in mice
Sergio Vaira, … , Roberta Faccio, Deborah Veis Novack
Sergio Vaira, … , Roberta Faccio, Deborah Veis Novack
Published May 8, 2008
Citation Information: J Clin Invest. 2008;118(6):2088-2097. https://doi.org/10.1172/JCI33392.
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Research Article Bone biology

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-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.

Authors

Sergio Vaira, Muhammad Alhawagri, Imani Anwisye, Hideki Kitaura, Roberta Faccio, Deborah Veis Novack

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Figure 1

RelA is important for basal and stimulated OC formation in vivo.

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RelA is important for basal and stimulated OC formation in vivo. (A) TRA...
(A) TRAP-stained sections of vertebrae from Rela+/+ and Rela–/– RCs 4 months after bone marrow reconstitution. Scale bar: 100 μm. (B) Histomorphometric analysis was performed on TRAP-stained sections to determine the OC number (N.Oc./mm) and OC surface (Oc.S./BS.). *P < 0.05; n = 8/group. (C) Rela+/+ and Rela–/– RCs were injected with 100-μg RANKL or PBS daily for 5 days and sacrificed on the sixth day. TRAP-stained coronal sections of calvaria at the sagittal suture show a consistent increase in OCs along sutures and sinusoids only in Rela+/+ RANKL-treated animals. Scale bar: 200 μm. (D) Quantification of the N.Oc./mm and Oc.S./BS. (percentage of bone surface covered by OCs) along calvarial surfaces of mice in C confirms the significant difference in response of Rela+/+ and Rela–/– RCs to RANKL injection. In the PBS-injected animals, only rare OCs are detected in either genotype. †P < 0.005; n = 5/group. (E) Serum levels of TRAP5b were determined 1 day prior to first RANKL injection (baseline) and at sacrifice on day 6 (RANKL). ‡P = 0.01; n = 5/group.