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NF-κB p100 limits TNF-induced bone resorption in mice by a TRAF3-dependent mechanism
Zhenqiang Yao, … , Lianping Xing, Brendan F. Boyce
Zhenqiang Yao, … , Lianping Xing, Brendan F. Boyce
Published September 21, 2009
Citation Information: J Clin Invest. 2009;119(10):3024-3034. https://doi.org/10.1172/JCI38716.
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Research Article Article has an altmetric score of 3

NF-κB p100 limits TNF-induced bone resorption in mice by a TRAF3-dependent mechanism

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Abstract

TNF and RANKL mediate bone destruction in common bone diseases, including osteoarthritis and RA. They activate NF-κB canonical signaling directly in osteoclast precursors (OCPs) to induce osteoclast formation in vitro. However, unlike RANKL, TNF does not activate the alternative NF-κB pathway efficiently to process the IκB protein NF-κB p100 to NF-κB p52, nor does it appear to induce osteoclast formation in vivo in the absence of RANKL. Here, we show that TNF limits RANKL- and TNF-induced osteoclast formation in vitro and in vivo by increasing NF-κB p100 protein accumulation in OCPs. In contrast, TNF induced robust osteoclast formation in vivo in mice lacking RANKL or RANK when the mice also lacked NF-κB p100, and TNF-Tg mice lacking NF-κB p100 had more severe joint erosion and inflammation than did TNF-Tg littermates. TNF, but not RANKL, increased OCP expression of TNF receptor–associated factor 3 (TRAF3), an adapter protein that regulates NF-κB p100 levels in B cells. TRAF3 siRNA prevented TNF-induced NF-κB p100 accumulation and inhibition of osteoclastogenesis. These findings suggest that upregulation of TRAF3 or NF-κB p100 expression or inhibition of NF-κB p100 degradation in OCPs could limit bone destruction and inflammation-induced bone loss in common bone diseases.

Authors

Zhenqiang Yao, Lianping Xing, Brendan F. Boyce

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Figure 5

TNF-induced NF-κB p100 inhibits RANKL-induced osteoclastogenesis.

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TNF-induced NF-κB p100 inhibits RANKL-induced osteoclastogenesis.
(A) WT...
(A) WT mouse spleen cells were cultured with M-CSF for 3 days, and RANKL and/or TNF were added at the indicated doses for 2 more days to generate osteoclasts. Top: TNF dose-dependently inhibited RANKL-induced osteoclastogenesis, assessed by osteoclast number (black bars) and area (red bars) per well. Bottom: The protein levels of NF-κB p100 and p52 were analyzed with Western blot and assessed in whole-cell lysates extracted from RANKL-treated (10 ng/ml) and/or TNF-treated (20 ng/ml) WT mouse OCPs at 8 hours. (B) The inhibitory effect of TNF on RANKL-induced osteoclastogenesis was abolished in Nfkb2–/– OCPs (*P < 0.05 vs. RANKL treatment alone; 4 wells/group). The same experiments were repeated at least twice with similar results.

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

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