Increased HSD11β1 Expression in Human Leiomyomatous Uteri: Implication for Enhanced Glucocorticoid Signaling
Abstract
Context
FK506-binding-protein-51 (FKBP51) is a glucocorticoid-induced co-chaperone protein previously shown to bind glucocorticoid receptor (GR), inhibiting its transcriptional activity. We previously found increased FKBP51 levels in uterine leiomyoma vs paired myometrium.
Objective
To test the hypothesis that elevated FKBP51 levels contribute to leiomyoma pathogenesis by altering GR signaling.
Design
RNA-sequencing was performed in leiomyoma cell cultures transfected with scramble or FKBP5-siRNA for 48 hours, then treated with vehicle or dexamethasone (DEX) for 24 hours. Differentially expressed genes, including HSD11B1, CNN1, and LAMA2 were analyzed by quantitative polymerase chain reaction. Hydroxysteroid 11-β dehydrogenase 1 (HSD11β1) expression was analyzed in leiomyoma, leiomyoma-adjacent paired myometrium, myometrium from patients without leiomyoma, and human endometrial stromal cells by quantitative polymerase chain reaction and immunohistochemistry.
Setting
University research institution.
Patients
Women with or without uterine leiomyoma.
Main Outcome Measures
HSD11B1 mRNA and protein levels in leiomyoma, paired myometrium, and normal myometrium.
Results
HSD11β1 expression was higher in paired myometrial and leiomyoma tissues vs normal myometrium (P < .02). DEX treatment increased HSD11B1 transcription in normal myometrial and human endometrial stromal cell cultures, but to a significantly greater extent in leiomyoma (P < .001). However, FKBP5-silencing blunted this DEX-induced HSD11B1 upregulation. DEX-treatment reduced LAMA2 and increased CNN1 levels (coding for extracellular matrix and smooth muscle proteins, respectively) in FKBP5-silenced vs scramble siRNA-transfected leiomyoma cultures.
Conclusion
FKBP51 not only inhibits but can augment GR-mediated transcription. Importantly, FKBP51-GR interactions increase HSD11B1 levels in leiomyoma cells, generating a pathological FKBP51-GR-HSD11β1 circle, altering transcription of downstream extracellular matrix and smooth muscle genes to induce a myofibroblast phenotype, thereby possibly contributing to leiomyoma pathogenesis.
