Deficiency of immunophilin FKBP52 promotes endometriosis.
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.
Hirota
Yasushi
Y
Department of Pediatrics, Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA.
Tranguch
Susanne
S
Daikoku
Takiko
T
Hasegawa
Akiko
A
Osuga
Yutaka
Y
Taketani
Yuji
Y
Dey
Sudhansu K
SK
D000818:Animals; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004715:Endometriosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004717:Endometrium / Q000378:metabolism / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic; D011374:Progesterone / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000172:deficiency* / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D047628:Estrogen Receptor alpha; D011980:Receptors, Progesterone; D042461:Vascular Endothelial Growth Factor A; D011374:Progesterone; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4