Deficiency of Immunophilin FKBP52 Promotes Endometriosis

Abstract

Endometriosis is a common gynecological disease that affects approximately 10% of women of childbearing age. It is characterized by endometrial growth outside the uterus and often results in inflamed lesions, pain, and reduced fertility. Although heightened estrogenic activity and/or reduced progesterone responsiveness are considered to be involved in the etiology of endometriosis, neither the extent of their participation nor the underlying mechanisms are clearly understood. Heterogeneous uterine cell types differentially respond to estrogen and progesterone (P 4 ). P 4 , primarily acting via its nuclear receptor (PR), activates gene transcription and impacts many reproductive processes. Deletion of Fkbp52, an immunophilin cochaperone for PR, results in uterine-specific P 4 resistance in mice, creating an opportunity to study the unique aspects of P 4 signaling in endometriosis. Here we explored the roles of FKBP52 in this disease using Fkbp52 ؊/؊ mice. We found that the loss of FKBP52 encourages the growth of endometriotic lesions with increased inflammation , cell proliferation , and angiogenesis. We also found remarkable down-regulation of FKBP52 in cases of human endometriosis. Our results provide the first evidence corroborated by genetic studies in mice for a potential role of an immunophilin cochaperone in the etiology of human endometriosis. This investigation is highly relevant for clinical application , particularly because P 4 resistance is favorably indicated in endometriosis and other gynecological diseases.

FKBP4 is regulated by HOXA10 during decidualization and in endometriosis

“…This question was approached initially by confirming a report that FKBP4 mRNA levels are significantly lower in menstrual cycle-matched specimens of eutopic endometrium of women with endometriosis compared with endometriosis-free women (Hirota et al 2008) and extending these observations to include FKBP5. Subsequently, in vitro experiments evaluated the HOXA10, FKBP4, and FKBP5 mRNA and protein expressions and FKBP4 mRNA levels in the endometrium of women with and without endometriosis.…”

“…However, only implantation and decidualization are impaired in Fkbp4 knockout mice, indicating the selectivity and specificity of FKBP4 in mediating these progestin effects . Eutopic and ectopic endometria of women with endometriosis show significantly lower FKBP4 levels in both glands and stromal cells compared with women without endometriosis (Hirota et al 2008). Moreover, lower FKBP4 levels are reported in the endometria of baboons with experimentally induced endometriosis (Jackson et al 2007).…”

“…Fkbp4 K/K mice have reduced P 4 binding to PR, diminished PR transcriptional activity, and down-regulation of several P 4 -regulated genes in the uterus . Women with endometriosis show diminished levels of FKBP4 (Hirota et al 2008). P 4 resistance is an established risk factor for endometriosis, suggesting that insufficient FKBP4 expression elicits PR dysfunction and that the resulting P 4 resistance leads to endometriosis.…”

Uterine FK506-binding protein 52 (FKBP52)–peroxiredoxin-6 (PRDX6) signaling protects pregnancy from overt oxidative stress

“…Because our recent study has shown that FKBP52 levels are downregulated in endometria of women with endometriosis compared with women without endometriosis (29), reduced FKBP52 levels may lead to endometrial PRDX6 deficiency, increasing uterine susceptibility to ROS, aggravating endometriosis, and adversely affecting endometrial receptivity in patients with endometriosis.…”

“…Quantitative PCR was performed as previously described (29). A housekeeping gene Gapdh was used as an internal standard.…”