Deficiency of Immunophilin FKBP52 Promotes Endometriosis
Open accessAbstract
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.
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FKBP52 may promote endometriosis, as women with endometriosis show reduced FKBP52 expression, and progesterone resistance observed in 52KO mice results in increased cell proliferation, inflammation, and angiogenesis, leading to endometriotic lesions.
“Finally, FKBP52 may promote endometriosis, as women with endometriosis show reduced FKBP52 expression, and the progesterone resistance, observed in 52KO mice, results in increased cell proliferation, inflammation, and angiogenesis, leading to endometriotic lesions [37].”
From FKBP51 and FKBP52 in signaling and disease (2011) · cites this paper as [37]
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Cites
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Progesterone Receptor Isoform A But Not B Is Expressed in Endometriosis
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The Hsp90‐binding peptidylprolyl isomerase FKBP52 potentiates glucocorticoid signaling in vivo
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Cochaperone immunophilin FKBP52 is critical to uterine receptivity for embryo implantation
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Self-citationPhysiological role for the cochaperone FKBP52 in androgen receptor signaling
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“Functionally mature steroid hormone receptors including that of PR consist of a receptor monomer, a 90-kDa heat shock protein (Hsp90) dimer, the cochaperone p23, and one of the four cochaperones containing a tetratricopeptide repeat that binds to Hsp90.”
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“Likely, FK506 is considered to affect other steroid receptor activities.(69,70) Although there is no report that FK506 influences the incidence and development of endometriosis, it may be prudent to address this issue, because endometriosis is considered an immunological disorder.”
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“In fact, the immunosuppressant drug FK506, which binds immunophilins FKBP51 and FKBP52, inhibits androgen receptor activity in prostate cancer cells.(67) Likely, FK506 is considered to affect other steroid receptor activities.”
BackgroundPotentiation of progesterone receptor-mediated transcription by the immunosuppressant FK506.
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FKBP51 and FKBP52 in signaling and disease
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“Finally, FKBP52 may promote endometriosis, as women with endometriosis show reduced FKBP52 expression, and the progesterone resistance, observed in 52KO mice, results in increased cell proliferation, inflammation, and angiogenesis, leading to endometriotic lesions [37].”
Mechanisms of endometrial progesterone resistance
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Regulation of steroid hormone receptor function by the 52-kDa FK506-binding protein (FKBP52)
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Self-citation
- Authors
- Hirota, Y., Tranguch, S., Daikoku, T., Hasegawa, A., Osuga, Y., Taketani, Y., & Dey, S. K.
- Affiliations
- The University of Tokyo (JP)
- Vanderbilt University Medical Center (US)
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Dey, Sudhansu K.
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2008-12
- Volume
- 173
- Issue
- 6
- Pages
- 1747-1757
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC2626386
- OpenAlex
- W2019014038
- Cited by
- 67
- References
- 11
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 4 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 2 · 2017: 3 · 2016: 4 · 2015: 4 · 2014: 7 · 2013: 2 · 2012: 6
- FWCI
- 6.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Vanderbilt University
- National Institutes of Health (HD12304, DA06668)
- Japan Society for the Promotion of Science
- National Institute on Drug Abuse (DA06668, R01DA006668, R37DA006668)
- National Cancer Institute (P01CA077839)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R37HD012304, 2T HD007043, T32HD007043, HD-12304)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Plant and fungal interactions
- Keywords
- endometriosis, FKBP52, progesterone resistance, progesterone receptor, endometriotic lesion growth, inflammation, cell proliferation, angiogenesis, estrogen signaling, progesterone signaling
- MeSH terms
- Animals, Disease Models, Animal, Endometriosis, Endometrium, Female, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Neovascularization, Pathologic, Progesterone, Receptors, Progesterone, Chemokine CCL2, Tacrolimus Binding Proteins, Vascular Endothelial Growth Factor A, Estrogen Receptor alpha, Cell Proliferation, Mice, Cyclooxygenase 2
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