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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

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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 5

Knockdown of Bid rescues Rela–/– osteoclastogenesis.

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Knockdown of Bid rescues Rela–/– osteoclastogenesis.
   
(A) Rela+/+ and...
(A) Rela+/+ and Rela–/– BMMs were stimulated with RANKL at the indicated times, and total cell lysates were examined by immunoblot for expression of Bid. β-actin was used as loading control. (B) Rela–/– BMMs were transduced with retrovirus expressing 2 different siRNAs for Bid (siBid1 and siBid2) or luciferase (siLuc). Following puromycin selection, levels of Bid were examined by immunoblot, demonstrating reduction of Bid by the specific siRNAs. β-actin was used as loading control. (C) Rela+/+ and Rela–/– BMMs transduced with siLuc or siBid1 or -2 were cultured with RANKL for 36 hours and DNA fragmentation was measured. The data are representative of 3 independent experiments. *P < 0.05 versus Rela+/+ siLuc. (D) The same BMMs in C were cultured in osteoclastogenic conditions for 6 days, then stained for TRAP, showing rescue of differentiation with knockdown of Bid. Scale bar: 200 μm. (E) BMMs cultured on cortical bone slices were stained with horseradish peroxidase-conjugated wheat germ agglutinin to demonstrate resorption. Scale bar: 200 μm. (F) Pits in E were quantified, showing that reduction in apoptosis correlates with differentiation and bone resorption. Black bars indicate Rela+/+; gray bars indicate Rela–/–; *P < 0.05 versus Rela+/+ siLuc.

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