Decoy oligodeoxynucleotides targeting NF-kappaB transcription factors: induction of apoptosis in human primary osteoclasts

Penolazzi, Letizia; Lambertini, Elisabetta; Borgatti, Monica; Piva, Roberta; Cozzani, Mauro; Giovannini, Ilaria; Naccari, Rosalba; Siciliani, Gíuseppe; Gambari, Roberto

doi:10.1016/s0006-2952(03)00470-2

Cited by 47 publications

(41 citation statements)

References 51 publications

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“…Consistent with the results of our study, an NF-nB decoy oligonucleotide significantly stimulated apoptosis, upregulated caspase-3, and inhibited IL-6 expression in osteoclasts (52). This kind of decoy could decrease the numbers of osteoclasts available to induce osteolytic bone destruction and simultaneously suppress tumorigenic effects dependent on NF-nB activation (52,53).…”

Section: Discussionsupporting

confidence: 90%

Nuclear Factor-κB–Dependent Mechanisms in Breast Cancer Cells Regulate Tumor Burden and Osteolysis in Bone

et al. 2005

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A central mediator of a wide host of target genes, the nuclear factor-KB (NF-KB) family of transcription factors, has emerged as a molecular target in cancer and diseases associated with bone destruction. To evaluate how NF-KB signaling in tumor cells regulates processes associated with osteolytic bone tumor burden, we stably infected the boneseeking MDA-MB-231 breast cancer cell line with a dominant-negative mutant IKB that prevents phosphorylation of IKBa and associated nuclear translocation of NF-KB. Blockade of NF-KB signaling in MDA-MB-231 cells by the mutant IKB decreased in vitro cell proliferation, expression of the proinflammatory, bone-resorbing cytokine interleukin-6, and in vitro bone resorption by tumor/osteoclast cocultures while reciprocally up-regulating production of the proapoptotic enzyme caspase-3. Suppression of NF-KB transcription in these breast cancer cells also reduced incidence of in vivo tumor-mediated osteolysis after intratibial injection of tumor cells in female athymic nude mice. Immunohistochemistry showed that the cancerous lesions formed in bone by MDA-MB-231 cells express both interleukin-6 and the p65 subunit of NF-KB at the bone-tumor interface. NF-KB signaling in breast cancer cells therefore promotes bone tumor burden and tumor-mediated osteolysis through combined control of tumor proliferation, cell survival, and bone resorption. These findings imply that NF-KB and its associated genes may be relevant therapeutic targets in osteolytic tumor burden. (Cancer Res 2005; 65(8): 3209-17)

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Section: Discussionsupporting

confidence: 90%

Nuclear Factor-κB–Dependent Mechanisms in Breast Cancer Cells Regulate Tumor Burden and Osteolysis in Bone

et al. 2005

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“…Of importance, the uptake of NFkB decoy ODN was relatively restricted in macrophage/monocyte cells in this study, because of phagocytotic activity. Consist with previous report, 14 NFkB decoy ODN may selectively induce cell death in monocyte/macrophage cells and thus in osteoclasts of all their differentiation stages. These phenomena come out to be great advantages considering the side effect to other cell types especially to osteoblasts, since all decoy ODN used in this experiments were trasfected in naked style.…”

Section: Discussionsupporting

confidence: 81%

NFκB decoy oligodeoxynucleotides ameliorates osteoporosis through inhibition of activation and differentiation of osteoclasts

et al. 2006

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The transcription factor, nuclear factor-kappa B (NFkB), is believed to play a pivotal role in osteoclast formation. In this study, we focused on NFkB decoy oligodeoxynucleotides (ODN) as a new therapeutic strategy to attenuate osteoporosis. Tartrate-resistant acid phosphatase (TRAP)-positive multinuclear osteoclasts formed in mononuclear cells including osteoclast precursors from neonatal rabbit bone marrow were increased in the presence of 1,25-dihydroxyvitamin D3, whereas transfection of NFkB decoy ODN decreased the number of TRAP-positive cells and attenuated RANKL and M-CSF-induced osteoclast formation. NFkB decoy ODN also inhibited the activity of osteoclasts, as assessed by pit formation. In rat overiectomized model of estrogen deficiency, continuous administration of NFkB decoy ODN attenuated the increase of TRAP activity, accompanied by a significant increase in calcium concentration in tibia and femur and decrease in urinary deoxypyridinoline. In additional osteoporosis model using vitamin C-deficient rat, inhibition of NFkB by decoy ODN dramatically improved the bone length, weight, density as assessed by dual-energy X-ray absorptiometry. Overall, inhibition of NFkB by decoy strategy prevented osteoporosis through the inhibition of bone resorption. Targeting of NFkB might be potential therapy in various bone metabolic diseases. Gene Therapy (2006) 13, 933-941.

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“…Interestingly, human osteoclasts have been shown to require NFκB for survival, supporting that targeting this survival factor is a common mechanism to support survival of human and murine osteoclasts [48]. Recently, this same group published that human osteoclasts differentiated from cord blood responded differently to apoptosis induction than human osteoclasts differentiated from peripheral blood, suggesting that the source of human cells must be carefully evaluated in human osteoclast survival studies [49].…”

Section: Discussionmentioning

confidence: 99%

TGF-β coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promote osteoclast survival

Gingery

Bradley

Pederson

et al. 2008

Experimental Cell Research

163

120

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To better understand the roles of TGF-β in bone metabolism, we investigated osteoclast survival in response TGF-β and found that TGF-β inhibited apoptosis. We examined the receptors involved in promotion of osteoclast survival and found that the canonical TGF-β receptor complex is involved in the survival response. The upstream MEK kinase TAK1 was rapidly activated following TGF-β treatment. Since osteoclast survival involves MEK, AKT, and NFκB activation, we examined TGF-β effects on activation of these pathways and observed rapid phosphorylation of MEK, AKT, IKK, IκB, and NFκB. The timing of activation coincided with SMAD activation and dominant negative SMAD expression did not inhibit NFκB activation, indicating that kinase pathway activation is independent of SMAD signaling. Inhibition of TAK1, MEK, AKT, NIK, IKK, or NFκB repressed TGF-β-mediated osteoclast survival. Adenoviral-mediated TAK1 or MEK inhibition eliminated TGF-β-mediated kinase pathway activation and constitutively active AKT expression overcame apoptosis induction following MEK inhibition. TAK1/MEK activation induces pro-survival BclX L expression and TAK1/MEK and SMAD pathway activation induces pro-survival Mcl-1 expression. These data show that TGF-β-induced NFκB activation is through TAK1/MEK-mediated AKT activation, which is essential for TGF-β to support of osteoclast survival.

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Decoy oligodeoxynucleotides targeting NF-kappaB transcription factors: induction of apoptosis in human primary osteoclasts

Cited by 47 publications

References 51 publications

Nuclear Factor-κB–Dependent Mechanisms in Breast Cancer Cells Regulate Tumor Burden and Osteolysis in Bone

Nuclear Factor-κB–Dependent Mechanisms in Breast Cancer Cells Regulate Tumor Burden and Osteolysis in Bone

NFκB decoy oligodeoxynucleotides ameliorates osteoporosis through inhibition of activation and differentiation of osteoclasts

TGF-β coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promote osteoclast survival

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