https://orcid.org/0009-0007-2939-8883
Abstract
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.
To test the hypothesis that elevated FKBP51 levels contribute to leiomyoma pathogenesis by altering GR signaling.
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.
University-Research institution
Women with or without uterine leiomyoma
None
HSD11B1 mRNA and protein levels in leiomyoma, paired myometrium, and normal myometrium.
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.
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.
Accepted manuscripts
