Heard Melissa E, Velarde Michael C, Giudice Linda C, Simmen Frank A, Simmen Rosalia C M
Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Department of Obstetrics, Gynecology & Reproductive Sciences, University of California San Francisco, San Francisco, California.
Biol Reprod. 2015 Jun;92(6):140. doi: 10.1095/biolreprod.115.130260. Epub 2015 Apr 22.
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/Hedgehog-associated 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.
Krüppel样因子（KLF）13以及与之密切相关的KLF9是Sp/KLF转录因子家族的成员，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。类固醇激素反应性组织表达多种KLF，它们作为整合因子或共调节因子与孕激素受体（PGR）和雌激素受体（ESR）的作用相关联。子宫内膜异位症是一种以孕激素抵抗和雌二醇信号失调为特征的慢性疾病；然而，不同KLF成员对子宫内膜异位症的贡献在很大程度上仍不明确。我们之前在子宫内膜异位症小鼠模型中证明了Klf9基因敲除的子宫内膜可促进异位病灶的形成。在此，我们评估了子宫内膜细胞中KLF13表达缺失是否同样会导致病灶形成。在月经中期分泌期，患有子宫内膜异位症的女性在位内膜中的KLF13转录水平低于未患该病的女性。在野生型（WT）小鼠受体腹腔内注射WT或Klf13基因敲除的子宫内膜碎片后，病灶发生率与供体基因型无关。病灶体积、数量、增殖状态和凋亡指数也未观察到差异。与WT病灶相比，Klf13基因敲除的病灶显示总PGR和ESR1（RNA和免疫反应性蛋白）减少，并且几个PGR和ESR1靶基因的表达发生改变。与Klf9基因敲除的病灶不同，Klf13基因敲除的病灶未观察到PGR-A、ESR1以及Notch/ Hedgehog相关信号通路成分转录水平的变化。结果表明，小鼠子宫内膜KLF13缺乏与病灶形成之间不存在因果关系，并且它们支持除类固醇受体介导的信号通路之外，多种信号通路在子宫内膜异位症病理过程中发挥更广泛的作用。
