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 versus 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-h, then treated with vehicle or dexamethasone (DEX) for 24-h. Differentially expressed genes, including HSD11B1, CNN1, and LAMA2 were analyzed by qPCR. Hydroxysteroid 11-beta dehydrogenase 1 (HSD11β1) expression was analyzed in leiomyoma, leiomyoma-adjacent paired myometrium, myometrium from patients without leiomyoma, and human endometrial stromal cells (HESC) by qPCR and immunohistochemistry.

Setting: University-Research institution.

Patients: Women with or without uterine leiomyoma.

Interventions: None.

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 versus normal myometrium (P<0.02). DEX treatment increased HSD11B1 transcription in normal myometrial and HESC cultures, but to a significantly greater extent in leiomyoma (P<0.001). 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 versus scramble siRNA-transfected leiomyoma cultures.

Conclusions: 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.