Deficiency of Immunophilin FKBP52 Promotes Endometriosis

Yasushi Hirota^*, Susanne Tranguch^*, Takiko Daikoku^*, Akiko Hasegawa, Yutaka Osuga, Yuji Taketani and Sudhansu K. Dey^*

From the Departments of Pediatrics,^* Cell & Developmental Biology, Pharmacology, Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee; and the Department of Obstetrics & Gynecology, Faculty of Medicine, University of Tokyo, Tokyo, Japan

Endometriosis is a common gynecological disease that affectsapproximately 10% of women of childbearing age. It is characterizedby endometrial growth outside the uterus and often results ininflamed lesions, pain, and reduced fertility. Although heightenedestrogenic activity and/or reduced progesterone responsivenessare considered to be involved in the etiology of endometriosis,neither the extent of their participation nor the underlyingmechanisms are clearly understood. Heterogeneous uterine celltypes differentially respond to estrogen and progesterone (P₄).P₄, primarily acting via its nuclear receptor (PR), activatesgene transcription and impacts many reproductive processes.Deletion of Fkbp52, an immunophilin cochaperone for PR, resultsin uterine-specific P₄ resistance in mice, creating an opportunityto study the unique aspects of P₄ 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 growthof endometriotic lesions with increased inflammation, cell proliferation,and angiogenesis. We also found remarkable down-regulation ofFKBP52 in cases of human endometriosis. Our results providethe first evidence corroborated by genetic studies in mice fora potential role of an immunophilin cochaperone in the etiologyof human endometriosis. This investigation is highly relevantfor clinical application, particularly because P₄ resistanceis favorably indicated in endometriosis and other gynecologicaldiseases.