Targeting FKBP51 prevents stress-induced preterm birth.

Abstract

Preterm birth (PTB) is a leading cause of perinatal morbidity and mortality, with maternal stress-related disorders, such as depression and anxiety, linked to idiopathic PTB (iPTB). At the maternal-fetal interface, decidualized stromal cells (DSCs) exclusively express the progesterone receptor (PR) and play pivotal roles in maintaining pregnancy and initiating labor. DSCs also express FKBP51, a protein that binds to and inhibits transcriptional activity of glucocorticoid and PR receptors and is associated with stress-related diseases. We previously found that iPTB specimens exhibit increased FKBP51 levels and enhanced FKBP51-PR interactions in DSC nuclei. Additionally, we demonstrated that Fkbp5-deficient mice have prolonged gestation and are resistant to stress-induced PTB, suggesting that FKBP51 contributes to iPTB pathogenesis. Since no FDA-approved therapy exists for PTB, we hypothesized that inhibiting FKBP51 could prevent iPTB. Our current results show that the endogenous prostaglandin D2 derivative 15dPGJ2 reduces FKBP51 levels and FKBP51-PR interactions in cultured cells. Maternal stress increases uterine expression of Fkbp5, Oxtr, and Akr1c18, leading to shortened gestation. However, treatment with 15dPGJ2 lowers uterine Fkbp51, Oxtr, and Ptgs2 levels and prevents stress-induced PTB. Notably, co-treatment with 15dPGJ2 and either P4 or R5020 produced the most significant effects, highlighting the potential of 15dPGJ2 alone or in combination with progestins as a promising therapeutic strategy to prevent PTB.