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A novel role of the Sp/KLF transcription factor KLF11 in arresting progression of endometriosis. PLoS One 2013;8(3):e60165

Date

04/05/2013

Pubmed ID

23555910

Pubmed Central ID

PMC3610699

DOI

10.1371/journal.pone.0060165

Scopus ID

2-s2.0-84875516286   32 Citations

Abstract

Endometriosis affects approximately 10% of young, reproductive-aged women. Disease associated pelvic pain; infertility and sexual dysfunction have a significant adverse clinical, social and financial impact. As precise disease etiology has remained elusive, current therapeutic strategies are empiric, unfocused and often unsatisfactory. Lack of a suitable genetic model has impaired further translational research in the field. In this study, we evaluated the role of the Sp/KLF transcription factor KLF11/Klf11 in the pathogenesis of endometriosis. KLF11, a human disease-associated gene is etiologically implicated in diabetes, uterine fibroids and cancer. We found that KLF11 expression was diminished in human endometriosis implants and further investigated its pathogenic role in Klf11-/- knockout mice with surgically induced endometriotic lesions. Lesions in Klf11-/- animals were large and associated with prolific fibrotic adhesions resembling advanced human disease in contrast to wildtype controls. To determine phenotype-specificity, endometriosis was also generated in Klf9-/- animals. Unlike in Klf11-/- mice, lesions in Klf9-/- animals were neither large, nor associated with a significant fibrotic response. KLF11 also bound to specific elements located in the promoter regions of key fibrosis-related genes from the Collagen, MMP and TGF-I? families in endometrial stromal cells. KLF11 binding resulted in transcriptional repression of these genes. In summary, we identify a novel pathogenic role for KLF11 in preventing de novo disease-associated fibrosis in endometriosis. Our model validates in vivo the phenotypic consequences of dysregulated Klf11 signaling. Additionally, it provides a robust means not only for further detailed mechanistic investigation but also the ability to test any emergent translational ramifications thereof, so as to expand the scope and capability for treatment of endometriosis.

Author List

Daftary GS, Zheng Y, Tabbaa ZM, Schoolmeester JK, Gada RP, Grzenda AL, Mathison AJ, Keeney GL, Lomberk GA, Urrutia R

Authors

Gwen Lomberk PhD Professor in the Surgery department at Medical College of Wisconsin
Angela Mathison PhD Assistant Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis Regulatory Proteins
Blotting, Western
Collagen
DNA-Binding Proteins
Endometriosis
Endometrium
Female
Humans
Immunohistochemistry
Kruppel-Like Transcription Factors
Matrix Metalloproteinases
Mice
Mice, Knockout
Polymerase Chain Reaction
Repressor Proteins
Stromal Cells
Tissue Array Analysis
Transcription Factors
Transforming Growth Factor beta