FKBP51 Contributes to Uterine Leiomyoma Pathogenesis by Inducing Cell Proliferation and Extracellular Matrix Deposition

Abstract

The FK506-binding protein 51 (FKBP51) binds progesterone receptor (PR), glucocorticoid receptor (GR), and androgen receptor (AR) to coregulate their transcriptional activity. We evaluated FKBP51 expression and function in human leiomyoma vs. myometrial tissues and primary cultures to discover FKBP51 role(s) in the pathogenesis of leiomyomas. Quantification of in situ FKBP51 mRNA and protein levels inpaired myometrial vs. leiomyoma tissues from proliferative and secretory phases were analyzed by qPCR (n = 14), immunoblotting (n = 20), and immunohistochemistry (n = 12). Control (scramble) vs. FKBP5 siRNA-transfected leiomyoma cell cultures were assessed for proliferation, apoptosis, and mRNA levels of genes involved in cell survival and extracellular matrix (ECM) formation. Significantly higher FKBP5 mRNA levels were detected in leiomyoma vs. paired myometrium (P < 0.001). Immunoblot (P = 0.001) and immunostaining (P ≤ 0.001) confirmed increased FKBP51 levels in leiomyoma vs. paired myometrium. Compared to control siRNA transfection, FKBP5-silenced leiomyoma cell cultures displayed significantly decreased cell survival factors and reduced proliferation (P < 0.05). Moreover, qPCR analysis revealed significantly lower mRNA levels of ECM, TIPM1, and TIPM3 proteins in FKBP5-silenced leiomyoma cell cultures (P < 0.05). Increased FKBP51 expression in leiomyoma likely involves dysregulation of steroid signaling by blocking GR and PR action and promoting proliferation and ECM production. Evaluating the effect of FKBP51 inhibition in preclinical studies will clarify its significance as a potential therapeutic approach against leiomyoma.Supplementary InformationThe online version contains supplementary material available at 10.1007/s43032-022-00921-2.