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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 2

Rela–/– RCs are protected from arthritis-induced bone loss.

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Rela–/– RCs are protected from arthritis-induced bone loss.
   
(A) Art...
(A) Arthritis was induced in Rela+/+ and Rela–/– RCs 5 weeks after marrow transplantation by injection of K/BxN serum at days 0, 2, and 7, with LPS on day 2. Histological sections of ankle joints at day 14 stained with H&E show an extensive and similar inflammatory infiltrate in the joint spaces. Scale bar: 500 μm. (B) The inflammatory response was also evaluated by measurement of hind paw thickness (sum of both paws) during induction of arthritis. n = 8/group. The experiment was repeated twice, with similar results. (C) TRAP-stained sections of metatarsals demonstrate OCs both on the outer bone surface adjacent to inflammatory pannus (arrowheads) and in marrow spaces. Scale bar: 100 μm. (D) Histomorphometric analysis of N.Oc./mm and Oc.S./BS. on the outer bone surface demonstrate significantly more OCs in Rela+/+ RCs compared with Rela–/– RCs. *P < 0.001; n = 8/group. (E) Serum CTX was measured at day 0 and 14 of serum transfer arthritis, and the fold change for each RC was plotted, demonstrating a significant rise only in the Rela+/+ group. †P < 0.05; n = 6/group.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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