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 Endometriosis1

Abstract

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-like factor 12 is a novel negative regulator of forkhead box O1 expression: a potential role in impaired decidualization

“…Furthermore, KLF9 deficiency in the uterus has been shown to promote the establishment of ectopic lesions in a mouse model of endometriosis [ 28 ]. Finally, KLF13-null lesions contribute to defective steroid hormone receptor signaling in the pathology of endometriosis [ 29 ], and KLF15 negatively regulates E2-induced epithelial cell proliferation, which is associated with endometriosis and endometrial cancer [ 30 ]. All of these reproductive diseases in which KLFs have been implicated are associated with impaired decidualization.…”

The Effects of Hedgehog Ligand Neutralising Antibody 5E1 in a Mouse Model of Endometriosis

“…Differences in hedgehog pathway activation have been detected in women with endometriosis and mouse models of endometriosis 4,5,20 . This study aimed to see whether the hedgehog neutralising antibody 5E1 would prevent lesion establishment and progression in a mouse model of endometriosis.…”

Mouse model of menstruation: An indispensable tool to investigate the mechanisms of menstruation and gynaecological diseases (Review)

“…endometriosis is an oestrogen-dependent gynaecological disease that is caused by the implantation of viable endometrial cells outside the endometrium. The most common manifestations of this disease are progesterone resistance and abnormal oestradiol signalling (60). endometriosis is characterized by the presence of endometrial glands and extrauterine stroma.…”

“…Nonetheless, the total numbers of progesterone receptors, oestrogen receptors and eSr1 (rna and immune reactive protein) are low. Therefore, KlF13 may be involved in the pathological process of endometriosis (60).…”