NF-κB modulates activation of the BMP-2 gene by trichostatin A

Li, Xi; XiZhuang, Bai

doi:10.1134/s0026893308060071

Cited by 4 publications

(5 citation statements)

References 24 publications

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“…The ectopic expression of genes that normally drive appendage regenerative outgrowth is counter-intuitive because HDAC inhibition blocks regeneration. However, our observations are consistent with other studies which have shown that TSA treatment increases BMP2 mRNA level in human osteoclasts [42] and also up-regulates Notch1 expression in cancer cells resulting in growth suppression [43] . Our observation that TSA treatment de-regulates normal regenerative gene expression further suggests that the proper control of gene expression pattern is an important requirement for regeneration.…”

Section: Resultssupporting

confidence: 93%

“…4). This result was not unexpected since BMP2 mRNA has been demonstrated to increase in the presence of TSA treatment [42], and HDAC inhibitor treatment results in the up-regulation of Notch and suppressed cellular growth [43], [46]. Previous Xenopus work used constitutively-active forms of either the BMP receptor Alk3 or the intracellular active Notch domain (NICD) [13] to promote tail regeneration.…”

Section: Discussionmentioning

confidence: 88%

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HDAC Activity Is Required during Xenopus Tail Regeneration

et al. 2011

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The ability to fully restore damaged or lost organs is present in only a subset of animals. The Xenopus tadpole tail is a complex appendage, containing epidermis, muscle, nerves, spinal cord, and vasculature, which regenerates after amputation. Understanding the mechanisms of tail regeneration may lead to new insights to promote biomedical regeneration in non-regenerative tissues. Although chromatin remodeling is known to be critical for stem cell pluripotency, its role in complex organ regeneration in vivo remains largely uncharacterized. Here we show that histone deacetylase (HDAC) activity is required for the early stages of tail regeneration. HDAC1 is expressed during the 1st two days of regeneration. Pharmacological blockade of HDACs using Trichostatin A (TSA) increased histone acetylation levels in the amputated tail. Furthermore, treatment with TSA or another HDAC inhibitor, valproic acid, specifically inhibited regeneration. Over-expression of wild-type Mad3, a transcriptional repressor known to associate in a complex with HDACs via Sin3, inhibited regeneration. Similarly, expression of a Mad3 mutant lacking the Sin3-interacting domain that is required for HDAC binding also blocks regeneration, suggesting that HDAC and Mad3 may act together to regulate regeneration. Inhibition of HDAC function resulted in aberrant expression of Notch1 and BMP2, two genes known to be required for tail regeneration. Our results identify a novel early role for HDAC in appendage regeneration and suggest that modulation of histone acetylation is important in regenerative repair of complex appendages.

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 88%

HDAC Activity Is Required during Xenopus Tail Regeneration

et al. 2011

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“…43,44 On the other hand, nuclear factor B has been reported to activate BMP-2 expression in osteoblasts as well as in chondrocytes. 45,46 Therefore, activation of nuclear factor B might be a possible mechanism linking VSMCs dedifferentiation and enhanced BMP-2 expression.…”

Section: Discussionmentioning

confidence: 99%

Paracrine Osteogenic Signals via Bone Morphogenetic Protein-2 Accelerate the Atherosclerotic Intimal Calcification In Vivo

Nakagawa

Ikeda

Akakabe

et al. 2010

ATVB

115

105

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Objective-Vascular calcification is an important risk factor for cardiovascular diseases. Here, we investigated a role of dedifferentiated vascular smooth muscle cells (VSMCs) in the atherosclerotic intimal calcification. Methods and Results-We prepared human cultured VSMCs in either redifferentiatiated or dedifferentiated state and analyzed the gene expressions of bone-calcification regulatory factors. Expression of bone morphogenetic protein-2 (BMP-2), a potent initiator for osteoblast differentiation, was significantly enhanced in dedifferentiated VSMCs. Furthermore, endogenous BMP-2 antagonists, such as noggin, chordin, and matrix gamma-carboxyglutamic acid protein, were all downregulated in the dedifferentiated VSMCs. Conditioned medium from dedifferentiated VSMCs, but not from redifferentiated VSMCs, stimulated the osteoblastic differentiation of the mesenchymal progenitor C2C12 cells, which was abolished by BMP-2 knockdown. In atherosclerotic intima from apolipoprotein (apo)E-deficient mice, ␣SM-actin-positive cells, presumably dedifferentiated VSMCs, expressed BMP-2. We generated BMP-2-transgenic mice using ␣SM-actin promoter and crossed them with apoE-deficient mice (BMP-2-transgenic/apoE-knockout).Significantly accelerated atherosclerotic intimal calcification was detected in BMP-2-transgenic/apoE-knockout mice, although serum lipid concentration and atherosclerotic plaque size were not different from those in apoE-knockout mice. Enhanced calcification appeared to be associated with the frequent emergence of osteoblast-like cells in atherosclerotic intima in BMP-2-transgenic/apoE-knockout mice. V ascular calcification has been an important risk factor for cardiovascular diseases as well as all-causal mortality. 1,2 There are several types of vascular calcification, such as calcification in intima associated with atherosclerosis and calcification in tunica media (medial calcification), which is often observed in elderly people and patients with diabetes mellitus and/or chronic kidney disease. 3 Recently, we have reported an important role of senescent vascular smooth muscle cells (VSMCs) in the formation of medial calcification associated with aging. 4 However, the molecular mechanism(s) governing atherosclerotic intimal calcification remains to be elucidated. Atherosclerotic calcification of coronary artery is a significant risk for the unsuccessful coronary intervention and balloon-induced coronary artery dissection. 5 Calcification score of coronary arteries assessed by electron beam computer tomography has been reported to correlate well with the incidence of cardiovascular diseases. 6 Furthermore, calcification was found to be a reliable marker of plaque instability, defined as plaques that have undergone rupture using autopsy specimens. 7 However, there is a controversy around this with arguments describing calcification as a marker of plaque stability as well. Negative correlation between extensive calcification and plaque instability was shown, and the pattern of calcification rather than the vo...

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“…However, recent studies have demonstrated direct roles of NF-κB signaling to regulate OB differentiation and function. Critical signaling pathways and transcription factors are involved in embryonic osteoblastogenesis, including BMPs/Runx2 and Wnt-β-catenin, which interact with both canonical and non-canonical NF-κB signaling proteins [101][102][103]. The BMP2 promoter contains NF-κB responsive elements, which can be activated by acetylation of p65 and p50 proteins in OBs [102].…”

Section: Molecular Mechanisms By Which Nf-κb Signaling Regulates Oste...mentioning

confidence: 99%

“…Critical signaling pathways and transcription factors are involved in embryonic osteoblastogenesis, including BMPs/Runx2 and Wnt-β-catenin, which interact with both canonical and non-canonical NF-κB signaling proteins [101][102][103]. The BMP2 promoter contains NF-κB responsive elements, which can be activated by acetylation of p65 and p50 proteins in OBs [102]. BMPs are members of the TGFβsuperfamily, and binding of BMP to its receptor phosphorylates Smad1/5 or forms a Smad1/Smad4 complex to activate downstream signaling.…”

Section: Molecular Mechanisms By Which Nf-κb Signaling Regulates Oste...mentioning

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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NF-κB modulates activation of the BMP-2 gene by trichostatin A

Cited by 4 publications

References 24 publications

HDAC Activity Is Required during Xenopus Tail Regeneration

HDAC Activity Is Required during Xenopus Tail Regeneration

Paracrine Osteogenic Signals via Bone Morphogenetic Protein-2 Accelerate the Atherosclerotic Intimal Calcification In Vivo

Nuclear Factor-Kappa B Regulation of Osteoclastogenesis and Osteoblastogenesis

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