IL-6 and sIL-6R induces STAT3-dependent differentiation of human VSMCs into osteoblast-like cells through JMJD2B-mediated histone demethylation of RUNX2

Kurozumi, Akira; Nakano, Kazuhisa; Yamagata, Kazuya; Okada, Yosuke; Nakayamada, Shingo; Tanaka, Yoshiya

doi:10.1016/j.bone.2019.04.006

Cited by 79 publications

(49 citation statements)

References 40 publications

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“…Although the IC 50 values of JIB-04 ranged from 230 to 1100 nM for different histone demethylases 24 , we observed that TSCs exhibited growth inhibition and underwent apoptosis at 250 nM and 500 nM concentrations, respectively (data not shown). Therefore, we attempted to treat TSCs at a concentration ranged from 0-100 nM, which was reported to show biological responses on cell proliferation and gene expression [26][27][28] . Interestingly, it was observed that stemness-associated genes, including Cdx2, Eomes, and Elf5, were significantly downregulated by 2.5-3.5 folds at 50 nM JIB-04 treatment for 48 h, and their expressions were further decreased at 100 nM treatment in a dosage-dependent manner (Fig.…”

Section: Resultsmentioning

confidence: 99%

Histone demethylase JMJD2B/KDM4B regulates transcriptional program via distinctive epigenetic targets and protein interactors for the maintenance of trophoblast stem cells

Mak

Lam

2021

Sci Rep

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Trophoblast stem cell (TSC) is crucial to the formation of placenta in mammals. Histone demethylase JMJD2 (also known as KDM4) family proteins have been previously shown to support self-renewal and differentiation of stem cells. However, their roles in the context of the trophoblast lineage remain unclear. Here, we find that knockdown of Jmjd2b resulted in differentiation of TSCs, suggesting an indispensable role of JMJD2B/KDM4B in maintaining the stemness. Through the integration of transcriptome and ChIP-seq profiling data, we show that JMJD2B is associated with a loss of H3K36me3 in a subset of embryonic lineage genes which are marked by H3K9me3 for stable repression. By characterizing the JMJD2B binding motifs and other transcription factor binding datasets, we discover that JMJD2B forms a protein complex with AP-2 family transcription factor TFAP2C and histone demethylase LSD1. The JMJD2B–TFAP2C–LSD1 complex predominantly occupies active gene promoters, whereas the TFAP2C–LSD1 complex is located at putative enhancers, suggesting that these proteins mediate enhancer–promoter interaction for gene regulation. We conclude that JMJD2B is vital to the TSC transcriptional program and safeguards the trophoblast cell fate via distinctive protein interactors and epigenetic targets.

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Section: Resultsmentioning

confidence: 99%

Histone demethylase JMJD2B/KDM4B regulates transcriptional program via distinctive epigenetic targets and protein interactors for the maintenance of trophoblast stem cells

Mak

Lam

2021

Sci Rep

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“…These findings highlight the importance of pro-inflammatory macrophages in VC progression. Furthermore, interleukin-6 (IL-6)/soluble interleukin-6 receptor (sIL-6R) complexes induced transformation of human VSMCs into an osteoblast phenotype, resulting in subsequent VC [298]. Tumor necrosis factor alpha (TNF-α), and IL-1β, induced the endothelial-to-mesenchymal transition in human primary aortic endothelial cells, thereby promoting them for BMP-9-mediated osteogenic differentiation.…”

Section: Inflammation and Immune Dysregulation In The Pathogenesis Ofmentioning

confidence: 99%

Vascular Calcification—New Insights into Its Mechanism

Lee

Jeon

2020

IJMS

283

254

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Vascular calcification (VC), which is categorized by intimal and medial calcification, depending on the site(s) involved within the vessel, is closely related to cardiovascular disease. Specifically, medial calcification is prevalent in certain medical situations, including chronic kidney disease and diabetes. The past few decades have seen extensive research into VC, revealing that the mechanism of VC is not merely a consequence of a high-phosphorous and -calcium milieu, but also occurs via delicate and well-organized biologic processes, including an imbalance between osteochondrogenic signaling and anticalcific events. In addition to traditionally established osteogenic signaling, dysfunctional calcium homeostasis is prerequisite in the development of VC. Moreover, loss of defensive mechanisms, by microorganelle dysfunction, including hyper-fragmented mitochondria, mitochondrial oxidative stress, defective autophagy or mitophagy, and endoplasmic reticulum (ER) stress, may all contribute to VC. To facilitate the understanding of vascular calcification, across any number of bioscientific disciplines, we provide this review of a detailed updated molecular mechanism of VC. This encompasses a vascular smooth muscle phenotypic of osteogenic differentiation, and multiple signaling pathways of VC induction, including the roles of inflammation and cellular microorganelle genesis.

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“…We mainly focused on the relationship between miR-34a and the prototypical pro-inflammatory SASP component IL6, which is canonically upregulated in cells that have undergone senescence, increases with age and plays a causal role in inflammaging and age-related diseases [8,30,32,33]. Besides, IL6 is one of the most abundant cytokines produced by senescent VSMCs and exerts pro-calcification activity [8,34,35]. We found that miR-34a and IL6 levels are upregulated and positively correlate in aortas of old mice and with HASMCs donors' age and senescence (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

The microRNA-34a-Induced Senescence-Associated Secretory Phenotype (SASP) Favors Vascular Smooth Muscle Cells Calcification

Zuccolo

Badi

Scavello

et al. 2020

IJMS

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The senescence of vascular smooth muscle cells (VSMCs), characterized by the acquisition of senescence-associated secretory phenotype (SASP), is relevant for VSMCs osteoblastic differentiation and vascular calcification (VC). MicroRNA-34a (miR-34a) is a driver of such phenomena and could play a role in vascular inflammaging. Herein, we analyzed the relationship between miR-34a and the prototypical SASP component IL6 in in vitro and in vivo models. miR-34a and IL6 levels increased and positively correlated in aortas of 21 months-old male C57BL/6J mice and in human aortic smooth muscle cells (HASMCs) isolated from donors of different age and undergone senescence. Lentiviral overexpression of miR-34a in HASMCs enhanced IL6 secretion. HASMCs senescence and calcification accelerated after exposure to conditioned medium of miR-34a-overexpressing cells. Analysis of miR-34a-induced secretome revealed enhancement of several pro-inflammatory cytokines and chemokines, including IL6, pro-senescent growth factors and matrix-degrading molecules. Moreover, induction of aortas medial calcification and concomitant IL6 expression, with an overdose of vitamin D, was reduced in male C57BL/6J Mir34a−/− mice. Finally, a positive correlation was observed between circulating miR-34a and IL6 in healthy subjects of 20-90 years. Hence, the vascular age-associated miR-34a promotes VSMCs SASP activation and contributes to arterial inflammation and dysfunctions such as VC.

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IL-6 and sIL-6R induces STAT3-dependent differentiation of human VSMCs into osteoblast-like cells through JMJD2B-mediated histone demethylation of RUNX2

Cited by 79 publications

References 40 publications

Histone demethylase JMJD2B/KDM4B regulates transcriptional program via distinctive epigenetic targets and protein interactors for the maintenance of trophoblast stem cells

Histone demethylase JMJD2B/KDM4B regulates transcriptional program via distinctive epigenetic targets and protein interactors for the maintenance of trophoblast stem cells

Vascular Calcification—New Insights into Its Mechanism

The microRNA-34a-Induced Senescence-Associated Secretory Phenotype (SASP) Favors Vascular Smooth Muscle Cells Calcification

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