オカダ ヨウスケ   Okada Yosuke
  岡田 洋右
   所属   医学部医学科  臨床医学系 第1内科学
   職種   准教授
論文種別 原著
言語種別 英語
査読の有無 査読あり
表題 IL-6 and sIL-6R induces STAT3-dependent differentiation of human VSMCs into osteoblast-like cells through JMJD2B-mediated histone demethylation of RUNX2.
掲載誌名 正式名:Bone
略  称:Bone
ISSNコード:18732763/18732763
巻・号・頁 124,53-61頁
著者・共著者 Kurozumi Akira, Nakano Kazuhisa, Yamagata Kaoru, Okada Yosuke, Nakayamada Shingo, Tanaka Yoshiya
発行年月 2019/04
概要 Inflammation and vascular calcification are independent risk factors of cardiovascular events. Vascular smooth muscle cells (VSMCs) exhibit osteoblast-like characteristics in response to various stimuli such as oxidized cholesterol and inflammation. However the precise mechanism of transcriptional regulation of VSMCs by inflammatory stimuli remains unclear. We investigated the process and mechanisms of inflammatory cytokine-induced transformation of human VSMCs (hVSMCs) into osteoblast-like cells, with a special focus on epigenetic changes. Our results demonstrated: (1) interleukin-6 (IL-6)/soluble interleukin-6 receptor (sIL-6R) induced transformation of hVSMCs into an osteoblast phenotype, with subsequent vascular calcification, based on the results of Alizarin Red S staining and O-Cresolphthalein complexone method; (2) IL-6/sIL-6R accelerated the expression of runt-related transcription factor 2 (RUNX2) based on the results of quantitative real-time polymerase chain reaction; (3) Knockdown of signal transducer and activator of transcription (STAT) 3 reduced IL-6/sIL-6R-induced RUNX2 mRNA expression and osteoblast transdifferentiation of hVSMCs; (4) Chromatin immunoprecipitation (ChIP) coupled with PCR (ChIP-PCR) identified a STAT-binding site in RUNX2 promoter region containing trimethylated histone 3 lysine 9 (H3K9me3), a transcriptional repressor, and H3K4me3, a transcriptional enhancer. Stimulation with IL-6/sIL-6R suppressed H3K9me3 but not H3K4me3 through the recruitment of jumonji domain-containing protein (JMJD) 2B, a histone lysine demethylase, at the STAT-binding site in RUNX2 promoter region; (5) IL-6/sIL-6R-induced RUNX2 gene expression was inhibited in hVSMCs pretreated with JIB04, JMJD2 inhibitor, and the inhibitory effect was JIB04 dose-dependent. Our results indicate that the IL-6/STAT3/JMJD2B pathway regulates hVSMCs differentiation into osteoblast-like cells, which suggest its pathogenic role in vascular calcification associated with chronic infl
DOI 10.1016/j.bone.2019.04.006
PMID 30981888