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

Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Ave.,Rochester, NY 14642, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 09/2009; 119(10):3024-34. DOI: 10.1172/JCI38716
Source: PubMed


TNF and RANKL mediate bone destruction in common bone diseases, including osteoarthritis and RA. They activate NF-kappaB canonical signaling directly in osteoclast precursors (OCPs) to induce osteoclast formation in vitro. However, unlike RANKL, TNF does not activate the alternative NF-kappaB pathway efficiently to process the IkappaB protein NF-kappaB p100 to NF-kappaB 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-kappaB 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-kappaB p100, and TNF-Tg mice lacking NF-kappaB 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-kappaB p100 levels in B cells. TRAF3 siRNA prevented TNF-induced NF-kappaB p100 accumulation and inhibition of osteoclastogenesis. These findings suggest that upregulation of TRAF3 or NF-kappaB p100 expression or inhibition of NF-kappaB p100 degradation in OCPs could limit bone destruction and inflammation-induced bone loss in common bone diseases.

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    • "Thus, TNF-a was as effective as RANKL to stimulate osteoclast formation when the Traf3 gene was down-regulated by siRNA. TNF-a, which can not induce osteoclasts in vivo in Rank -/-mice, causes a robust stimulation of osteoclasts in Rank -/- / p100 -/-mice, further pointing to the important restrictive role of p100 for TNF-a induced osteoclast formation (Yao et al., 2009). As described above, IKKa is important for activation of the non-canonical pathway and IKKb for the canonical pathway. "
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    Immunological Investigations 10/2013; 42(7):555-622. DOI:10.3109/08820139.2013.822766 · 1.99 Impact Factor
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    • "These include primarily pathologic stimulators, chiefly TNF. In this regard, it has been demonstrated that aside from its RANKL-costimulatory osteoclastogenic function, TNF induces osteoclast formation in RANK/RANKL-deficient mice, in vivo, albeit in the absence of NF-κBp100 subunit [17]. More recently, we have demonstrated that an IKK2 gain of function mutation (IKK2 in which serines 177/181 were substituted with glutamates; namely IKK2SSEE) induces osteoclastogenesis independent of upstream RANK/RANKL and TNF/TNFr signaling [18]. "
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    ABSTRACT: Physiologic osteoclastogenesis entails activation of multiple signal transduction pathways distal to the cell membrane receptor RANK. However, atypical osteoclastogenesis driven by pro-inflammatory stimuli has been described. We have reported recently a novel mechanism whereby endogenous mutational activation of the classical NF-κB pathway is sufficient to induce RANKL/RANK-independent osteoclastogenesis. Here we investigate the physiologic relevance of this phenomenon in vivo. Using a knock-in approach, the active form of IKK2, namely IKK2SSEE, was introduced into the myeloid lineage with the aid of CD11b-cre mice. Phenotypic assessment revealed that expression of IKK2SSEE in the myeloid compartment induced significant bone loss in vivo. This observation was supported by a dramatic increase in the number and size of osteoclasts in trabecular regions, elevated levels of circulating TRACP-5b, and reduced bone volume. Mechanistically, we observed that IKK2SSEE induced high expression of not only p65 but also p52 and RelB; the latter two molecules are considered exclusive members of the alternative NF-κB pathway. Intriguingly, RelB and P52 were both required to mediate the osteoclastogenic effect of IKK2SSEE and co-expression of these two proteins was sufficient to recapitulate osteoclastogenesis in the absence of RANKL or IKK2SSEE. Furthermore, we found that NF-κB2/p100 is a potent inhibitor of IKK2SSEE-induced osteoclastogenesis. Deletion of p52 enabled more robust osteoclast formation by the active kinase. In summary, molecular activation of IKK2 may play a role in conditions of pathologic bone destruction, which may be refractory to therapeutic interventions targeting the proximal RANKL/RANK signal.
    PLoS ONE 06/2012; 7(6):e38694. DOI:10.1371/journal.pone.0038694 · 3.23 Impact Factor
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    • "On the other hand, recent emerging evidence shows that NF-κB p100 functions as a negative regulator of osteoclasto-genesis by binding to NF-κB complexes and preventing their nuclear translocation. Cytosolic accumulation of p100 impairs osteoclastogenesis, whereas p100 deficiency leads to enhanced osteoclastogenesis that contributes to an osteopenic phenotype in vivo [44,45]. TNF-α, unlike RANKL, does not seem to activate the alternative NF-κB pathway efficiently, as it induces an accumulation of p100 in osteoclast precursors via induction of TRAF3, thus limiting TNF-α-induced osteoclastogenesis [44]. "
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