Inhibition of BMP2-Induced Bone Formation by the p65 Subunit of NF-κB via an Interaction With Smad4

Hirata-Tsuchiya, Shizu; Fukushima, Hidefumi; Katagiri, Takenobu; Ohte, Satoshi; Shin, Masashi; Nagano, Kenichi; Aoki, Kazuhiro; Morotomi, Takahiko; Sugiyama, Goro; Nakatomi, Chihiro; Kokabu, Shoichiro; Doi, Takahiro; Takeuchi, Hiroshi; Ohya, Keiichi; Terashita, Masamichi; Hirata, Masato; Kitamura, Chiaki; Jimi, Eijiro

doi:10.1210/me.2014-1094

Cited by 40 publications

(51 citation statements)

References 41 publications

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“…We suggest that Ifrd1 deficiency inhibits the NF‐κB‐dependent transcription of Smad7 and subsequent activation of Smad1/Smad5/Smad8 signaling, leading to the promotion of osteoblastogenesis via Osx in osteoblasts. It has been demonstrated that the inhibition of NF‐κB promotes bone formation through the upregulation of JNK/Fra‐1, whereas p65 interacts with the Smad complex, subsequently disrupting its binding to target promoters and leading to the inhibition of Smad‐dependent transcription . We cannot exclude the possibility that Ifrd1–NF‐κB signaling regulates osteoblastogenesis through the JNK/Fra‐1 pathway or via direct regulation of the Smad pathway.…”

Section: Discussionmentioning

confidence: 93%

The Transcriptional Modulator Interferon-Related Developmental Regulator 1 in Osteoblasts Suppresses Bone Formation and Promotes Bone Resorption

Iezaki

Onishi

Ozaki

et al. 2015

Journal of Bone and Mineral Research

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Bone homeostasis is maintained by the synergistic actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Although interferon-related developmental regulator 1 (Ifrd1) has been identified as a transcriptional coactivator/repressor in various cells, little attention has been paid to its role in osteoblastogenesis and bone homeostasis thus far. Here, we show that Ifrd1 is a critical mediator of both the cell-autonomous regulation of osteoblastogenesis and osteoblast-dependent regulation of osteoclastogenesis. Osteoblast-specific deletion of murine Ifrd1 increased bone formation and decreased bone resorption, causing high bone mass. Ifrd1 deficiency enhanced osteoblast differentiation and maturation along with increased expression of Runx2 and osterix (Osx). Mechanistically, Ifrd1 deficiency increased the acetylation status of p65, a component of NF-kB, at residues K122 and K123 via the attenuation of the interaction between p65 and histone deacetylase (HDAC). This led to the nuclear export of p65 and a decrease in NF-kB-dependent Smad7 expression and the subsequent enhancement of Smad1/Smad5/Smad8-dependent transcription. Moreover, a high bone mass phenotype in the osteoblast-specific deletion of Ifrd1 was markedly rescued by the introduction of one Osx-floxed allele but not of Runx2-floxed allele. Coculture experiments revealed that Ifrd1-deficient osteoblasts have a higher osteoprotegerin (OPG) expression and a lower ability to support osteoclastogenesis. Ifrd1 deficiency attenuated the interaction between b-catenin and HDAC, subsequently increasing the acetylation of b-catenin at K49, leading to its nuclear accumulation and the activation of the b-catenin-dependent transcription of OPG. Collectively, the expression of Ifrd1 in osteoblasts repressed osteoblastogenesis and activated osteoclastogenesis through modulating the NF-kB/Smad/Osx and b-catenin/OPG pathways, respectively. These findings suggest that Ifrd1 has a pivotal role in bone homeostasis through its expression in osteoblasts in vivo and represents a therapeutic target for bone diseases.

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Section: Discussionmentioning

confidence: 93%

The Transcriptional Modulator Interferon-Related Developmental Regulator 1 in Osteoblasts Suppresses Bone Formation and Promotes Bone Resorption

Iezaki

Onishi

Ozaki

et al. 2015

Journal of Bone and Mineral Research

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“…Among the top 15 enriched TFs, there were a few which had previously been linked to BMP target gene regulation. For example, XBP1 and RELA have been shown to be repressors of BMP target genes Xvent-2 and Id1 , respectively [27, 28]. Using enrichment of the TFBSs between cell lines as well as other criteria, we selected three TFs (CBFB, HIF1A, and MBD2) for functional characterization and silenced them in the two cell lines.…”

Section: Discussionmentioning

confidence: 99%

Integrated RNA-seq and DNase-seq analyses identify phenotype-specific BMP4 signaling in breast cancer

et al. 2017

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BackgroundBone morphogenetic protein 4 (BMP4) plays an important role in cancer pathogenesis. In breast cancer, it reduces proliferation and increases migration in a cell line-dependent manner. To characterize the transcriptional mediators of these phenotypes, we performed RNA-seq and DNase-seq analyses after BMP4 treatment in MDA-MB-231 and T-47D breast cancer cells that respond to BMP4 with enhanced migration and decreased cell growth, respectively.ResultsThe RNA-seq data revealed gene expression changes that were consistent with the in vitro phenotypes of the cell lines, particularly in MDA-MB-231, where migration-related processes were enriched. These results were confirmed when enrichment of BMP4-induced open chromatin regions was analyzed. Interestingly, the chromatin in transcription start sites of differentially expressed genes was already open in unstimulated cells, thus enabling rapid recruitment of transcription factors to the promoters as a response to stimulation. Further analysis and functional validation identified MBD2, CBFB, and HIF1A as downstream regulators of BMP4 signaling. Silencing of these transcription factors revealed that MBD2 was a consistent activator of target genes in both cell lines, CBFB an activator in cells with reduced proliferation phenotype, and HIF1A a repressor in cells with induced migration phenotype.ConclusionsIntegrating RNA-seq and DNase-seq data showed that the phenotypic responses to BMP4 in breast cancer cell lines are reflected in transcriptomic and chromatin levels. We identified and experimentally validated downstream regulators of BMP4 signaling that relate to the different in vitro phenotypes and thus demonstrate that the downstream BMP4 response is regulated in a cell type-specific manner.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3428-1) contains supplementary material, which is available to authorized users.

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“…Osteoblasts are not only responsible for bone formation but are also capable of supporting osteoclast development by producing RANKL. 1,25-Dihydroxyvitamin D 3 (1,25[OH] 2 D 3 ) is a well-known factor that induces RANKL and suppresses OPG, a decoy receptor for RANKL. (1) Therefore, we determined whether Mst2 is associated with osteoblast-regulated osteoclast development by evaluating the expression of Tnfsf11 and Tnfrsf11b, which encode RANKL and OPG, respectively, in the presence of 1,25 (OH) 2 D 3 .…”

Section: Mst2 Is Not Involved In Osteoblast-mediated Osteoclastogenesismentioning

confidence: 99%

Mst2 Controls Bone Homeostasis by Regulating Osteoclast and Osteoblast Differentiation

Lee

Youn

Kim

et al. 2015

Journal of Bone and Mineral Research

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Mammalian sterile 20-like kinase 2 (Mst2) plays a central role in the Hippo pathway, controlling cell proliferation, differentiation, and apoptosis during development. However, the roles of Mst2 in osteoclast and osteoblast development are largely unknown. Here, we demonstrate that mice deficient in Mst2 exhibit osteoporotic phenotypes with increased numbers of osteoclasts and decreased numbers of osteoblasts as shown by micro-computed tomography (mCT) and histomorphometric analyses. Osteoclast precursors lacking Mst2 exhibit increased osteoclastogenesis and Nfatc1, Acp5, and Oscar expression in response to receptor activator of NF-kB ligand (RANKL) exposure. Conversely, Mst2 overexpression in osteoclast precursors leads to the inhibition of RANKL-induced osteoclast differentiation. Osteoblast precursors deficient in Mst2 exhibit attenuated osteoblast differentiation and function by downregulating the expression of Runx2, Alpl, Ibsp, and Bglap. Conversely, ectopic expression of Mst2 in osteoblast precursors increases osteoblastogenesis. Finally, we demonstrate that the NF-kB pathway is activated by Mst2 deficiency during osteoclast and osteoblast development. Our findings suggest that Mst2 is involved in bone homeostasis, functioning as a reciprocal regulator of osteoclast and osteoblast differentiation through the NF-kB pathway.

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Inhibition of BMP2-Induced Bone Formation by the p65 Subunit of NF-κB via an Interaction With Smad4

Cited by 40 publications

References 41 publications

The Transcriptional Modulator Interferon-Related Developmental Regulator 1 in Osteoblasts Suppresses Bone Formation and Promotes Bone Resorption

The Transcriptional Modulator Interferon-Related Developmental Regulator 1 in Osteoblasts Suppresses Bone Formation and Promotes Bone Resorption

Integrated RNA-seq and DNase-seq analyses identify phenotype-specific BMP4 signaling in breast cancer

Mst2 Controls Bone Homeostasis by Regulating Osteoclast and Osteoblast Differentiation

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