NF-{kappa}B p50 and p52 Regulate Receptor Activator of NF-{kappa}B Ligand (RANKL) and Tumor Necrosis Factor-induced Osteoclast Precursor Differentiation by Activating c-Fos and NFATc1

Department of Microbiology and Immunology, Keio University, Edo, Tōkyō, Japan
Journal of Biological Chemistry (Impact Factor: 4.57). 07/2007; 282(25):18245-53. DOI: 10.1074/jbc.M610701200
Source: PubMed

ABSTRACT Postmenopausal osteoporosis and rheumatoid joint destruction result from increased osteoclast formation and bone resorption induced by receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factor (TNF). Osteoclast formation induced by these cytokines requires NF-kappaB p50 and p52, c-Fos, and NFATc1 expression in osteoclast precursors. c-Fos induces NFATc1, but the relationship between NF-kappaB and these other transcription factors in osteoclastogenesis remains poorly understood. We report that RANKL and TNF can induce osteoclast formation directly from NF-kappaB p50/p52 double knockout (dKO) osteoclast precursors when either c-Fos or NFATc1 is expressed. RANKL- or TNF-induced c-Fos up-regulation and activation are abolished in dKO cells and in wild-type cells treated with an NF-kappaB inhibitor. c-Fos expression requires concomitant RANKL or TNF treatment to induce NFATc1 activation in the dKO cells. Furthermore, c-Fos expression increases the number and resorptive capacity of wild-type osteoclasts induced by TNF in vitro. We conclude that NF-kappaB controls early osteoclast differentiation from precursors induced directly by RANKL and TNF, leading to activation of c-Fos followed by NFATc1. Inhibition of NF-kappaB should prevent RANKL- and TNF-induced bone resorption.

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    • "In addition, recent studies have shown that the upregulation of RANKL-induced c-Fos is abrogated in NF-κB p50/p52 double-knockout osteoclast cell lineages, and osteoclast precursors from these mutant mice can differentiate into osteoclasts in response to RANKL when c-Fos is overexpressed, demonstrating that c-Fos is downstream of NF-κB in RANKL-mediated osteoclastogenesis (Yamashita et al., 2007). RANKL-induced NFATc1 expression is also defective in NF-κB p50/p52-deficient cells (Yamashita et al., 2007), and treatment with an NF-κB inhibitor attenuates the expression of NFATc1 induced by RANKL (Takatsuna et al., 2005), indicating that NFATc1 is also a key target gene of NF-κB during osteoclast differentiation. "
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    ABSTRACT: AimsOsteoclasts, the unique bone-resorbing polykaryons, are responsible for many bone-destructive diseases, such as osteoporosis and rheumatoid arthritis. Hence, the regulation of osteoclast formation is considered a potential therapeutic approach for these diseases. In this study, we investigated the effect of a novel small compound, C25H32N4O4S2 (NecroX-7) on osteoclast formation.Main methodsWe analyzed the effects of NecoX-7 on receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclast differentiation in vitro and LPS-induced bone loss in vivo.Key findingsWe observed that NecroX-7 suppressed osteoclast formation from primary bone marrow macrophages (BMMs) in a dose-dependent manner. NecroX-7 significantly inhibited the NF-κB signaling pathway without affecting the activation of the mitogen-activated protein kinases (MAPKs) JNK, p38, and ERK in response to RANKL. In addition, NecroX-7 strongly attenuated the induction of c-Fos and nuclear factor of activated T cells c1 (NFATc1), which are crucial transcription factors for osteoclast differentiation. Mirroring the down-regulation of c-Fos and NFATc1, the expression of osteoclastogenic markers, such as tartrate-resistant acid phosphatase (TRAP) and cathepsin K, was also reduced by the addition of NecroX-7. Furthermore, confirming the in vitro anti-osteoclastogenic effect, NecroX-7 inhibited lipopolysaccharide (LPS)-induced bone loss in vivo.SignificanceOur data imply that NecroX-7 is useful as a therapeutic drug for the treatment of bone resorption-associated diseases.
    Life sciences 11/2012; 91(s 19–20):928–934. DOI:10.1016/j.lfs.2012.09.009 · 2.30 Impact Factor
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    • "regulates gene transcription for osteoclastogenesis [5] [6]. "
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    ABSTRACT: Hwangryun-haedok-tang (HRT) is the common recipe in traditional Asian medicine, and microbial fermentation is used for the conventional methods for processing traditional medicine. We investigated the inhibitory effect of the n-butanol fraction of HRT (HRT-BU) and fHRT (fHRT-BU) on the RANKL-induced osteoclastogenesis in bone-marrow-derived macrophages. mRNA expression of osteoclastogenesis-related genes were evaluated by real-time QPCR. The activation of signaling pathways was determined by western blot analysis. The marker compounds of HRT-BU and fHRT-BU were analyzed by HPLC. The inhibitory effect of HRT or fHRT on ovariectomy-induced bone loss were evaluated using OVX rats with orally administered HRT, fHRT (300, 1000 mg/kg), or its vehicle for 12 weeks. fHRT-BU significantly inhibited RANKL-induced osteoclastogenesis, and phosphorylation of p38, IKKα/β, and NF-κBp65 compared to HRT-BU. In addition, fHRT-BU also significantly inhibited the mRNA expression of Nfκb2, TNF-α, NFATc1, TRAP, ATPv0d2, and cathepsin K. Furthermore, administration of fHRT had a greater effect on the increase of BMD, and greater improved bone microstructure of the femora than that of HRT in ovariectomy rats. This study demonstrated that bacterial fermentation enhances the inhibitory effect of HRT on osteoclastogenesis and bone loss. These results suggest that fermented HRT might have the beneficial effects on bone disease by inhibiting osteoclastogenesis.
    Evidence-based Complementary and Alternative Medicine 10/2012; 2012:325791. DOI:10.1155/2012/325791 · 1.88 Impact Factor
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    • "Given that the RANKL/ RANK axis and TNF-a participate in osteoclastogenesis by upregulating osteoclast activity, it can be concluded that a more resorptive microenvironment was created in CS. Moreover, TNF-a is an apoptotic factor for osteoblasts and osteocytes (Suda et al., 2001; Yamashita et al., 2007; Yano et al., 2005). This cytokine may also be a signal for osteoclast recruitment and, consequently, bone resorption (Burger et al., 2003). "
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    ABSTRACT: During orthodontic tooth movement (OTM), alveolar bone is resorbed by osteoclasts in compression sites (CS) and is deposited by osteoblasts in tension sites (TS). The aim of this study was to develop a standardized OTM protocol in mice and to investigate the expression of bone resorption and deposition markers in CS and TS. An orthodontic appliance was placed in C57BL6/J mice. To define the ideal orthodontic force, the molars of the mice were subjected to forces of 0.1N, 0.25N, 0.35N and 0.5N. The expression of mediators that are involved in bone remodeling at CS and TS was analyzed using a Real-Time PCR. The data revealed that a force of 0.35N promoted optimal OTM and osteoclast recruitment without root resorption. The levels of TNF-α, RANKL, MMP13 and OPG were all altered in CS and TS. Whereas TNF-α and Cathepsin K exhibited elevated levels in CS, RUNX2 and OCN levels were higher in TS. Our results suggest that 0.35N is the ideal force for OTM in mice and has no side effects. Moreover, the expression of bone remodeling markers differed between the compression and the tension areas, potentially explaining the distinct cellular migration and differentiation patterns in each of these sites.
    Journal of Biomechanics 10/2012; 45(16). DOI:10.1016/j.jbiomech.2012.09.006 · 2.50 Impact Factor
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