Constitutive activation of NF-κB inducing kinase (NIK) in the mesenchymal lineage using Osterix (Sp7)- or Fibroblast-specific protein 1 (S100a4)-Cre drives spontaneous soft tissue sarcoma

Davis, Jennifer L.; Thaler, Roman; Cox, Linda; Ricci, Biancamaria; Zannit, Heather M.; Wan, Fei; Faccio, Roberta; Dudakovic, Amel; Wijnen, André J. van; Veis, Deborah J.

doi:10.1371/journal.pone.0254426

Cited by 5 publications

(5 citation statements)

References 64 publications

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“…In tumor bearing mice, Osterix , as well as the Osx-Cre allele, is also expressed in a subset of cancer-associated fibroblasts with a dual fibroblast/osteogenic signature 27 . Recently, we found subcutaneous sarcomas, but not bone tumors, in mice expressing a transgene driven by Osterix-Cre 33 . Thus, it is possible that loss of IKKα in adipocytes themselves is responsible for the observed fat phenotype.…”

Section: Discussionmentioning

confidence: 99%

Conditional loss of IKKα in Osterix + cells has no effect on bone but leads to age-related loss of peripheral fat

Davis

Pokhrel

Cox

et al. 2022

Sci Rep

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NF-κB has been reported to both promote and inhibit bone formation. To explore its role in osteolineage cells, we conditionally deleted IKKα, an upstream kinase required for non-canonical NF-κB activation, using Osterix (Osx)-Cre. Surprisingly, we found no effect on either cancellous or cortical bone, even following mechanical loading. However, we noted that IKKα conditional knockout (cKO) mice began to lose body weight after 6 months of age with severe reductions in fat mass and lower adipocyte size in geriatric animals. qPCR analysis of adipogenic markers in fat pads of cKO mice indicated no difference in early differentiation, but instead markedly lower leptin with age. We challenged young mice with a high fat diet finding that cKO mice gained less weight and showed improved glucose metabolism. Low levels of recombination at the IKKα locus were detected in fat pads isolated from old cKO mice. To determine whether recombination occurs in adipocytes, we examined fat pads in Osx-Cre;TdT reporter mice; these showed increasing Osx-Cre-mediated expression in peripheral adipocytes from 6 weeks to 18 months. Since Osx-Cre drives recombination in peripheral adipocytes with age, we conclude that fat loss in cKO mice is most likely caused by progressive deficits of IKKα in adipocytes.

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Section: Discussionmentioning

confidence: 99%

Conditional loss of IKKα in Osterix + cells has no effect on bone but leads to age-related loss of peripheral fat

Davis

Pokhrel

Cox

et al. 2022

Sci Rep

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“…Pretreatment with a specific inhibitor impeded the MHC-instigated toxicity in the MCF-7 cells, indicating caspase-3 activation during the MHC-induced apoptosis. It is now an established notion that an NF-κB over-activation is related positively with several human cancers [33]. Moreover, it also plays an important role in regulating the transcriptional activation of anti-apoptotic genes [34].…”

Section: Discussionmentioning

confidence: 99%

“…The observations from the MTT assay elucidated that the MHC restricted the growth of the MDA-MB-231 cells by 85. 33…”

Section: Mhc Decreased Mcf-7 Cells Viabilitymentioning

confidence: 99%

3-Methoxy Carbazole Impedes the Growth of Human Breast Cancer Cells by Suppressing NF-κB Signaling Pathway

et al. 2022

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Breast cancer represents the most frequently occurring cancer globally among women. As per the recent report of the World Health Organization (WHO), it was documented that by the end of the year 2020, approximately 7.8 million females were positively diagnosed with breast cancer and in 2020 alone, 685,000 casualties were documented due to breast cancer. The use of standard chemotherapeutics includes the frontline treatment option for patients; however, the concomitant side effects represent a major obstacle for their usage. Carbazole alkaloids are one such group of naturally-occurring bioactive compounds belonging to the Rutaceae family. Among the various carbazole alkaloids, 3-Methoxy carbazole or C13H11NO (MHC) is obtained from Clausena heptaphylla as well as from Clausena indica. In this study, MHC was investigated for its anti-breast cancer activity based on molecular interactions with specific proteins related to breast cancer, where the MHC had predicted binding affinities for NF-κB with −8.3 kcal/mol. Furthermore, to evaluate the biological activity of MHC, we studied its in vitro cytotoxic effects on MCF-7 cells. This alkaloid showed significant inhibitory effects and induced apoptosis, as evidenced by enhanced caspase activities and the cellular generation of ROS. It was observed that a treatment with MHC inhibited the gene expression of NF-kB in MCF-7 breast cancer cells. These results suggest that MHC could be a promising medical plant for breast cancer treatment. Further studies are needed to understand the molecular mechanisms behind the anticancer action of MHC.

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“…Large and cystic tumor masses were detected in the submandibular region, on the trunk, perineal area, and rarely on the limbs, with a predominance in females. Development of soft tissue tumors is related to constitutive activation of the alternative NF-κB pathway, including RelB in mesenchymal lineage cells [ 94 ].…”

Section: Non-canonical Nf-κb Signaling In Osteoblastic Cellsmentioning

confidence: 99%

Nuclear Factor-Kappa B Regulation of Osteoclastogenesis and Osteoblastogenesis

Boyce,

Li,

Yao

et al. 2023

Endocrinol Metab

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Maintenance of skeletal integrity requires the coordinated activity of multinucleated bone-resorbing osteoclasts and bone-forming osteoblasts. Osteoclasts form resorption lacunae on bone surfaces in response to cytokines by fusion of precursor cells. Osteoblasts are derived from mesenchymal precursors and lay down new bone in resorption lacunae during bone remodeling. Nuclear factorkappa B (NF-κB) signaling regulates osteoclast and osteoblast formation and is activated in osteoclast precursors in response to the essential osteoclastogenic cytokine, receptor activator of NF-κB ligand (RANKL), which can also control osteoblast formation through RANK-RANKL reverse signaling in osteoblast precursors. RANKL and some pro-inflammatory cytokines, including tumor necrosis factor (TNF), activate NF-κB signaling to positively regulate osteoclast formation and functions. However, these cytokines also limit osteoclast and osteoblast formation through NF-κB signaling molecules, including TNF receptor-associated factors (TRAFs). TRAF6 mediates RANKL-induced osteoclast formation through canonical NF-κB signaling. In contrast, TRAF3 limits RANKL- and TNF-induced osteoclast formation, and it restricts transforming growth factor β (TGFβ)-induced inhibition of osteoblast formation in young and adult mice. During aging, neutrophils expressing TGFβ and C-C chemokine receptor type 5 (CCR5) increase in bone marrow of mice in response to increased NF-κB-induced CC motif chemokine ligand 5 (CCL5) expression by mesenchymal progenitor cells and injection of these neutrophils into young mice decreased bone mass. TGFβ causes degradation of TRAF3, resulting in decreased glycogen synthase kinase-3β/β-catenin-mediated osteoblast formation and age-related osteoporosis in mice. The CCR5 inhibitor, maraviroc, prevented accumulation of TGFβ+/CCR5+ neutrophils in bone marrow and increased bone mass by inhibiting bone resorption and increasing bone formation in aged mice. This paper updates current understanding of how NF-κB signaling is involved in the positive and negative regulation of cytokine-mediated osteoclast and osteoblast formation and activation with a focus on the role of TRAF3 signaling, which can be targeted therapeutically to enhance bone mass.

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Constitutive activation of NF-κB inducing kinase (NIK) in the mesenchymal lineage using Osterix (Sp7)- or Fibroblast-specific protein 1 (S100a4)-Cre drives spontaneous soft tissue sarcoma

Cited by 5 publications

References 64 publications

Conditional loss of IKKα in Osterix + cells has no effect on bone but leads to age-related loss of peripheral fat

Conditional loss of IKKα in Osterix + cells has no effect on bone but leads to age-related loss of peripheral fat

3-Methoxy Carbazole Impedes the Growth of Human Breast Cancer Cells by Suppressing NF-κB Signaling Pathway

Nuclear Factor-Kappa B Regulation of Osteoclastogenesis and Osteoblastogenesis

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