Progressive Fibrosis: A Progesterone- and KLF11-Mediated Sexually Dimorphic Female Response
| Autor: | Khashayarsha Khazaie, Zaraq Khan, Ye Zheng, Chandra C. Shenoy, Gaurang S. Daftary, T.L. Jones |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Gene Expression Cell Cycle Proteins Small hairpin RNA Mice 0302 clinical medicine Endocrinology Fibrosis Gene expression Medroxyprogesterone acetate RNA Small Interfering Progesterone Mice Knockout Estradiol Dihydrotestosterone DNA-Binding Proteins 030220 oncology & carcinogenesis Ovariectomized rat Androgens Female Peritoneum medicine.drug endocrine system medicine.medical_specialty Ovariectomy Medroxyprogesterone Acetate In Vitro Techniques Peritonitis Collagen Type I Cell Line 03 medical and health sciences Sex Factors In vivo Internal medicine medicine Animals Humans business.industry Estrogens medicine.disease Collagen Type I alpha 1 Chain Repressor Proteins 030104 developmental biology Sex steroid Progestins business Apoptosis Regulatory Proteins Transcription Factors |
| Zdroj: | Endocrinology. 158(10) |
| ISSN: | 1945-7170 |
| Popis: | 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 Kruppel-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. |
| Databáze: | OpenAIRE |
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