Krüppel-Like Factor 13 Deficiency in Uterine Endometrial Cells Contributes to Defective Steroid Hormone Receptor Signaling but Not Lesion Establishment in a Mouse Model of Endometriosis 1-猫眼课题宝

DOI：

发表时间：

2015

期刊：

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Melissa E. Heard;Michael C. Velarde;L. Giudice;F. Simmen;M. RosaliaC.;Simmen

Krüppel样因子（KLF）13和密切相关的KLF 9是Sp/KLF家族转录因子的成员，它们共同成为组织发育、分化、增殖和程序性细胞死亡的重要调节因子。类固醇激素反应组织表达多种KLF，这些KLF与孕激素受体（PGR）和雌激素受体（ESR）的作用相关，无论是作为整合剂还是作为共调节剂。子宫内膜异位症是一种以孕酮抵抗和雌二醇信号失调为特征的慢性疾病;然而，不同的KLF成员对子宫内膜异位症的贡献在很大程度上仍不明确。我们先前在子宫内膜异位症小鼠模型中证实了Klf 9缺失子宫内膜促进异位病变的建立。在这里，我们评估是否KLF 13在子宫内膜细胞表达的损失可能同样有助于病变的形成。子宫内膜异位症患者的子宫内膜KLF 13转录水平在月经中期分泌期较低。在野生型（WT）小鼠受体腹腔内注射WT或Klf 13无效子宫内膜片段，病变发生率与供体基因型没有差异。病变体积、数量、增殖状态和凋亡指数也无差异。Klf 13无效病变显示总PGR和ESR 1（RNA和免疫反应蛋白）减少，并改变了几个PGR和ESR 1靶基因的表达，相对于WT病变。与Klf 9无效病变不同，在Klf 13无效病变中未观察到PGR-A、ESR 1和Notch/Hedgehog相关途径组分的转录水平变化。结果表明，缺乏子宫内膜KLF 13缺陷和病变建立在小鼠之间的因果关系，他们支持更广泛的参与多种信号通路，除了类固醇受体介导的，在子宫内膜异位症的病理。子宫内膜异位症，雌激素受体，Krüppel样因子9，Krüppel样因子13，小鼠模型，孕激素受体简介子宫内膜异位症是一种良性雌激素（E2）依赖性疾病，其特征是子宫外存在子宫内膜组织。该病影响10%-15%的育龄妇女和高达50%的低生育力或不孕妇女[1]。子宫内膜异位症通常与慢性炎症，盆腔疼痛和初潮早期有关，并且它会给受影响的女性造成显著的情感，经济和身体负担[2]。虽然已经提出了关于子宫内膜异位症起源的几种理论，但最流行的是逆行月经，其中子宫内膜碎片在月经期间回流到腹膜腔[3]。后者得到了以下发现的支持，即卵巢在解剖学上位于逆行流出的直接路径，是子宫内膜异位症最常见的部位[4]。然而，由于逆行月经发生在.90%的女性中[5]，但只有10%患有子宫内膜异位症，其他致病因素可能在疾病的发展和进展中发挥作用。子宫内膜异位症的一个核心因素是子宫内膜孕酮（P 4）抵抗，这导致P 4反应靶基因和蛋白表达失调[6，7]。许多研究已经报道孕酮受体（PGR）和PGR辅调节因子表达的丧失与疾病建立相关。特别是，发现患有该疾病的女性的在位子宫内膜中PGR亚型PGR-A和PGR-B的水平比未患有该疾病的女性的在位子宫内膜低得多。此外，在异位病变中，观察到PGR-B相对于PGR-A的优先损失，导致更高的PGR-A：PGR-B表达比率[8-10]。PGR辅调节因子Hic-5、类固醇受体辅激活因子-1（SRC-1）和FKBP 52的表达水平降低也已在子宫内膜异位症女性的在位子宫内膜中得到描述，并且SRC-1和FKBP 52对疾病病理学的直接贡献最近已得到阐明在疾病的小鼠模型中[11-13]。我们的实验室先前已经描述了转录因子Krüppel样因子9（KLF 9）在子宫内稳态中的调节作用，这对于使用Klf 9缺失小鼠的妊娠和分娩很重要[14-16]。它与子宫疾病病理学的相关性已在另一种小鼠模型中得到支持[17]，更重要的是在女性中，其中其子宫内膜和子宫肌层表达的丧失与子宫内膜癌、子宫内膜异位症、子宫肌瘤和产程延长有关[18-22]。为了研究子宫内膜异位症和KLF 9缺失之间的因果关系，我们最近开发了一种小鼠模型，使用同基因免疫活性小鼠作为Klf 9缺失和相应野生型（WT）小鼠的供体子宫内膜的受体[23]。由Eunice Kennedy Shriver国家儿童健康和人类发展研究所（NICHD）向R.C.M.S.提供的HD21961赠款支持，和NICHD生殖和不孕症研究专业合作中心计划授予L.C.G. HD 055764（人类子宫内膜组织库）。通信：罗萨利亚CM西门，生理学和生物物理学系，4301西马卡姆街，小石城，阿肯色州72205。电子邮件：simmenrosalia@uams.edu。目前地址：巴克老龄化研究所，诺瓦托，加利福尼亚州。收稿日期：2015年3月26日。第一次决定：2015年4月11日。接受日期：2015年4月17日。2015年由社会的研究生殖，公司。eISSN：1529-7268 http://www.biolreprod.org ISSN：0006-3363

Krüppel-like Factor (KLF) 13 and the closely related KLF9 are members of the Sp/KLF family of transcription factors that have collectively emerged as essential regulators of tissue development, differentiation, proliferation, and programmed cell death. Steroid hormone-responsive tissues express multiple KLFs that are linked to progesterone receptor (PGR) and estrogen receptor (ESR) actions either as integrators or as coregulators. Endometriosis is a chronic disease characterized by progesterone resistance and dysregulated estradiol signaling; nevertheless, distinct KLF members’ contributions to endometriosis remain largely undefined. We previously demonstrated promotion of ectopic lesion establishment by Klf9 null endometrium in a mouse model of endometriosis. Here we evaluated whether KLF13 loss of expression in endometrial cells may equally contribute to lesion formation. KLF13 transcript levels were lower in the eutopic endometria of women with versus women without endometriosis at menstrual midsecretory phase. In wild-type (WT) mouse recipients intraperitoneally administered WT or Klf13 null endometrial fragments, lesion incidence did not differ with donor genotype. No differences were noted for lesion volume, number, proliferation status, and apoptotic index as well. Klf13 null lesions displayed reduced total PGR and ESR1 (RNA and immunoreactive protein) and altered expression of several PGR and ESR1 target genes, relative to WT lesions. Unlike for Klf9 null lesions, changes in transcript levels for PGR-A, ESR1, and Notch/Hedgehogassociated pathway components were not observed for Klf13 null lesions. Results demonstrate lack of a causative relationship between endometrial KLF13 deficiency and lesion establishment in mice, and they support the broader participation of multiple signaling pathways, besides those mediated by steroid receptors, in the pathology of endometriosis. endometriosis, estrogen receptor, Krüppel-like factor 9, Krüppellike factor 13, mouse model, progesterone receptor INTRODUCTION Endometriosis is a benign estrogen (E 2 )-dependent disease that is characterized by the presence of endometrial tissues outside of the uterus. The disease affects 10%–15% of reproductive-age women and up to 50% of women with subfertility or infertility [1]. Endometriosis is commonly associated with chronic inflammation, pelvic pain, and early menarche, and it causes a significant emotional, economic, and physical burden in affected women [2]. Although several theories on the origin of endometriosis have been proposed, the most prevalent relates to retrograde menstruation, in which endometrial fragments reflux back to the peritoneal cavity during menstruation [3]. The latter is supported by findings that the ovary, which is anatomically located in the direct path of the retrograde outflow, is the most common site of endometriosis [4]. Nevertheless, because retrograde menstruation occurs in .90% of women [5], yet only 10% have endometriosis, other causative factors likely play a role in the development and progression of the disease. A central element underlying endometriosis is endometrial progesterone (P 4 ) resistance, which leads to deregulated P 4 responsive target gene and protein expression [6, 7]. Numerous studies have reported the loss of expression of progesterone receptor (PGR) and PGR coregulators to be associated with disease establishment. In particular, the levels of PGR isoforms PGR-A and PGR-B were found to be comparably lower in the eutopic endometria of women with the disease than those without it. Moreover, in ectopic lesions the preferential loss of PGR-B relative to PGR-A, resulting in a higher PGR-A:PGR-B expression ratio, has been observed [8–10]. Reduced expression levels of PGR coregulators Hic-5, steroid receptor coactivator-1 (SRC-1), and FKBP52 have also been described in the eutopic endometria of women with endometriosis, and the direct contributions of SRC-1 and FKBP52 to disease pathology have been elucidated recently in mouse models of the disease [11–13]. Our laboratory has previously described the regulatory role of the transcription factor Krüppel-like factor 9 (KLF9) in uterine homeostasis, which is important for pregnancy and parturition using mice null for Klf9 [14–16]. Its relevance to the pathology of uterine diseases has been supported in another mouse model [17], and more importantly in women, wherein loss of its endometrial and myometrial expression was associated with endometrial cancer, endometriosis, myoma, and prolonged labor [18–22]. To investigate a causal relationship between endometriosis and loss of KLF9, we recently developed a mouse model using a syngeneic immunocompetent mouse as a recipient of donor endometria from Klf9 null and corresponding wild-type (WT) mice [23]. Supported by grant HD21961 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) to R.C.M.S., and the NICHD Specialized Cooperative Centers Program in Reproduction and Infertility Research grant HD055764 (Human Endometrial Tissue Bank) to L.C.G. Correspondence: Rosalia C.M. Simmen, Department of Physiology and Biophysics, 4301 West Markham St., Little Rock, AR 72205. E-mail: simmenrosalia@uams.edu. Current address: Buck Institute for Research on Aging, Novato, CA. Received: 26 March 2015. First decision: 11 April 2015. Accepted: 17 April 2015. 2015 by the Society for the Study of Reproduction, Inc. eISSN: 1529-7268 http://www.biolreprod.org ISSN: 0006-3363

Krüppel-Like Factor 13 Deficiency in Uterine Endometrial Cells Contributes to Defective Steroid Hormone Receptor Signaling but Not Lesion Establishment in a Mouse Model of Endometriosis 1

文献摘要

被引文献

相似文献