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
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. "
ABSTRACT: Chronic inflammatory processes close to bone often lead to loss of bone in diseases such as rheumatoid arthritis, periodontitis, loosened joint prosthesis and tooth implants. This is mainly due to local formation of bone resorbing osteoclasts which degrade bone without any subsequent coupling to new bone formation. Crucial for osteoclastogenesis is stimulation of mononuclear osteoclast progenitors by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) which induces their differentiation along the osteoclastic lineage and the fusion to mature, multinucleated osteoclasts. M-CSF and RANKL are produced by osteoblasts/osteocytes and by synovial and periodontal fibroblasts and the expression is regulated by pro- and anti-inflammatory cytokines. These cytokines also regulate osteoclastic differentiation by direct effects on the progenitor cells. In the present overview, we introduce the basic concepts of osteoclast progenitor cell differentiation and summarize the current knowledge on cytokines stimulating and inhibiting osteoclastogenesis by direct and indirect mechanisms.
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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 . 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 . "
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.
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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 . "
ABSTRACT: Bone remodeling in physiological and pathological conditions represents a balance between bone resorption mediated by osteoclasts and bone formation by osteoblasts. Bone resorption is tightly and dynamically regulated by multiple mediators, including cytokines that act directly on osteoclasts and their precursors, or indirectly by modulating osteoblast lineage cells that in turn regulate osteoclast differentiation. The critical role of cytokines in inducing and promoting osteoclast differentiation, function and survival is covered by the accompanying review by Zwerina and colleagues. Recently, it has become clear that negative regulation of osteoclastogenesis and bone resorption by inflammatory factors and cytokines, downstream signaling pathways, and a newly described network of transcriptional repressors plays a key role in bone homeostasis by fine tuning bone remodeling and restraining excessive bone resorption in inflammatory settings. In this review we discuss negative regulators of osteoclastogenesis and mechanisms by which these factors suppress bone resorption.