Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Bayern, Germany.
Department of Dermatology, Venereology, and Allergology, HELIOS St Elisabeth Hospital Oberhausen, University Witten-Herdecke, Germany.
Ann Rheum Dis. 2018 Jan;77(1):150-158. doi: 10.1136/annrheumdis-2017-211501. Epub 2017 Oct 25.
Systemic sclerosis (SSc) fibroblasts remain activated even in the absence of exogenous stimuli. Epigenetic alterations are thought to play a role for this endogenous activation. Trimethylation of histone H3 on lysine 27 (H3K27me3) is regulated by Jumonji domain-containing protein 3 (JMJD3) and ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) in a therapeutically targetable manner. The aim of this study was to explore H3K27me3 demethylases as potential targets for the treatment of fibrosis.
JMJD3 was inactivated by small interfering RNA-mediated knockdown and by pharmacological inhibition with GSKJ4. The effects of targeted inactivation of JMJD3 were analysed in cultured fibroblasts and in the murine models of bleomycin-induced and topoisomerase-I (topoI)-induced fibrosis. H3K27me3 at the promoter was analysed by ChIP.
The expression of JMJD3, but not of UTX, was increased in fibroblasts in SSc skin and in experimental fibrosis in a transforming growth factor beta (TGFβ)-dependent manner. Inactivation of JMJD3 reversed the activated fibroblast phenotype in SSc fibroblasts and prevented the activation of healthy dermal fibroblasts by TGFβ. Pharmacological inhibition of JMJD3 ameliorated bleomycin-induced and topoI-induced fibrosis in well-tolerated doses. JMJD3 regulated fibroblast activation in a FRA2-dependent manner: Inactivation of JMJD3 reduced the expression of FRA2 by inducing accumulation of H3K27me3 at the promoter. Moreover, the antifibrotic effects of JMJD3 inhibition were reduced on knockdown of .
We present first evidence for a deregulation of JMJD3 in SSc. JMJD3 modulates fibroblast activation by regulating the levels of H3K27me3 at the promoter of . Targeted inhibition of JMJD3 limits the aberrant activation of SSc fibroblasts and exerts antifibrotic effects in two murine models.
系统性硬化症 (SSc) 成纤维细胞即使在没有外源性刺激的情况下也保持激活状态。表观遗传改变被认为在这种内源性激活中起作用。组蛋白 H3 赖氨酸 27 三甲基化 (H3K27me3) 的调节由 Jumonji 结构域包含蛋白 3 (JMJD3) 和普遍转录的四肽重复序列 X 染色体 (UTX) 以可治疗的方式进行。本研究的目的是探索 H3K27me3 去甲基化酶作为纤维化治疗的潜在靶点。
通过小干扰 RNA 介导的敲低和通过 GSKJ4 进行药理学抑制来失活 JMJD3。在培养的成纤维细胞中和博来霉素诱导和拓扑异构酶 I (topoI) 诱导的纤维化的小鼠模型中分析靶向失活 JMJD3 的效果。通过 ChIP 分析 H3K27me3 在启动子上的情况。
在 SSc 皮肤中的成纤维细胞中和 TGFβ 依赖性实验性纤维化中，JMJD3 的表达增加，但 UTX 表达未增加。JMJD3 的失活逆转了 SSc 成纤维细胞中激活的成纤维细胞表型，并防止了 TGFβ 对健康真皮成纤维细胞的激活。JMJD3 的药理学抑制以可耐受的剂量改善了博来霉素诱导和 topoI 诱导的纤维化。JMJD3 通过 FRA2 依赖性方式调节成纤维细胞的激活：JMJD3 的失活通过诱导 H3K27me3 在启动子上的积累减少了 FRA2 的表达。此外，JMJD3 抑制的抗纤维化作用在 敲低的情况下降低。
我们首次证明 JMJD3 在 SSc 中失调。JMJD3 通过调节启动子上 H3K27me3 的水平来调节成纤维细胞的激活。JMJD3 的靶向抑制限制了 SSc 成纤维细胞的异常激活，并在两种小鼠模型中发挥抗纤维化作用。
