NF-κB p50 and p52 Regulate Receptor Activator of NF-κB Ligand (RANKL) and Tumor Necrosis Factor-induced Osteoclast Precursor Differentiation by Activating c-Fos and NFATc1
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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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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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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ABSTRACT: Osteoporosis is a growing healthcare burden that affects the quality of life in the aging population. Vitamin E is a potential prophylactic agent that can impede the progression of osteoporosis. Various in vivo studies demonstrated the antiosteoporotic potential of vitamin E, but evidence on its molecular mechanism of action is limited. A few in vitro studies showed that various forms of vitamin E can affect the receptor activator of nuclear factor kappa-B ligand (RANKL) signaling and their molecular targets, thus preventing the formation of osteoclasts in the early stage of osteoclastogenesis. Various studies have also shown that the effects of the different isoforms of vitamin E differ. The effects of single isoforms and combinations of isoforms on bone metabolism are also different. Vitamin E may affect bone metabolism by disruption of free radical-mediated RANKL signaling, by its oestrogen-like effects, by its effects on the molecular mechanism of bone formation, by the anti-inflammatory effects of its long-chain metabolites on bone cells, and by the inhibition of 3-hydroxyl-3-methyglutaryl coenzyme A (HMG-CoA). In conclusion, the vitamin E isoforms have enormous potential to be used as prophylactic and therapeutic agents in preventing osteoporosis, but further studies should be conducted to elucidate their mechanisms of action.Evidence-based Complementary and Alternative Medicine 08/2012; 2012:747020. DOI:10.1155/2012/747020 · 2.18 Impact Factor