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

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.

Higher fibrotic content of endometriotic lesions is associated with diminished prostaglandin E2 signaling

“…It might be possible that the hormonal treatment received earlier could still exert on endometriotic lesions, leaving a lingering effect on the extent of lesional fibrosis. Indeed, progesterone is shown to be pro‐fibrotic in endometriosis when KLF11 is deficient, 56 although it is unclear as whether or not the progestogens or combined progesterone/estrogen treatment alone can impact on the extent of lesional fibrosis. Fulvestrant (an estrogen antagonist) and micronized progesterone also have been shown to reduce post‐opeartive adhesion (a form of fibrosis) formation 57 .…”

Krϋppel-like factors (KLFs) in renal physiology and disease

“…Krüppel-like factor 10 (KLF10), originally named TGF-β (Transforming growth factor beta) inducible early gene 1 (TIEG1), and KLF11 regulate the TGF-βsignal transduction pathway [57]. While KLF10 modulates fibrosis in dystrophic skeletal muscles [58], endometriosis-related fibrosis is regulated by KLF11 [59]. However, the role of KLF10 and KLF11 in modulating kidney fibrosis is not investigated.…”

Reviewing the Regulators of COL1A1

“…Beyond the TGFβ pathway, an influence of male and female sex hormones on collagen regulation has been suggested based on observed differences in the incidence of fibrosis between males and females [ 68 ]. In testosterone deficient mice, injected testosterone and oestrogen were able to reduce Col1a1 mRNA expression leading to a less pronounced fibrosis phenotype [ 69 ].…”

“…In the context of endometriosis-related fibrosis, primary human peritoneal mesothelial cells in which Sp/KLF transcription factor Krüppel-like factor 11 (KLF11) was knocked down, treatment with progesterone resulted in an increase in COL1A1 mRNA levels, whereas conversely a decrease of the COL1A1 mRNA levels following treatment with oestrogen was noted. KLF11 knock-down by itself did not result in any significant changes in COL1A1 mRNA expression [ 68 ]. If these observations are confirmed in additional studies, they may form the basis for sex-specific recommendations for disease screening and early diagnosis as well as provide a window of opportunity for hormone therapy for fibrotic diseases [ 68 , 69 ].…”