Progressive Fibrosis: A Progesterone- and KLF11-Mediated Sexually Dimorphic Female Response

Chandra C. Shenoy, Khan Z, Zaraq Khan, Zheng Y, Ye Zheng, T.L. Jones, Tiffanny L Jones, Jones TL, Khashayarsha Khazaie, Khazaie K, Daftary GS, Gaurang S. Daftary
Endocrinology · 2017 · vol. 158(10) , pp. 3605–3619 · doi:10.1210/en.2017-00171 · PMID:28938437 · W2743251856
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Progesterone and KLF11 mediate a sexually dimorphic fibrotic response specifically in female mice, which is mitigated by antiprogestin therapy.

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Abstract

Progressive scarring is ubiquitous postoperatively and in an array of chronic systemic diseases. Recent studies indicate that such scarring has a high female propensity; females are also almost exclusively affected by endometriosis, a common sex steroid-dependent fibrotic disease. Endometriosis-related fibrosis is regulated epigenetically through transcription factor Krüppel-like factor 11 (KLF11). In response to surgical induction of endometriosis, Klf11-/- female mice develop significant fibrosis in contrast to wild-type mice. We therefore hypothesized that female fibrotic predilection was mediated by differential sex steroid regulation of KLF11/collagen 1a1 signaling and investigated the fibrotic response in wild-type and Klf11-/- male and female animals using a sterile peritonitis model. Fibrosis selectively developed in Klf11-/- females. Fibrosis in these animals was almost completely abrogated by ovariectomy. Ovariectomized animals were selectively supplemented with estradiol, medroxyprogesterone acetate (MPA), or dihydrotestosterone; fibrosis was only observed in mice exposed to MPA. Fibrosis therefore selectively developed in Klf11-/- female mice in response to physiological or pharmacological progesterone. The fibrotic response in these animals was also mitigated in response to antiprogestin therapy. Profibrotic gene expression was activated in a primary human peritoneal cell line in response to KLF11 short hairpin RNA and MPA but not estradiol. KLF11/collagen 1a1 signaling previously shown to be linked to fibrosis was thus selectively dysregulated in MPA-treated cells. Our in vivo and in vitro findings in an animal model and human cells, respectively, suggest that progressive fibrotic scarring is a sexually dimorphic response irrespective of etiology; moreover, it is responsive to novel, individualized therapeutic intervention.

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Condition tags

endometriosis

MeSH descriptors

DNA-Binding Proteins Fibrosis Peritoneum Progesterone Transcription Factors Androgens Androgens Animals Apoptosis Regulatory Proteins Cell Cycle Proteins Cell Cycle Proteins Cell Line Collagen Type I Collagen Type I Collagen Type I, alpha 1 Chain Dihydrotestosterone Dihydrotestosterone DNA-Binding Proteins Estradiol Estradiol

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