Targeting FKBP51 prevents stress-induced preterm birth

Area of Science:

• Reproductive biology
• Molecular endocrinology
• Perinatal medicine

Background:

• Preterm birth (PTB) is a major cause of infant mortality, with maternal stress contributing to idiopathic PTB (iPTB).
• Decidualized stromal cells (DSCs) express progesterone receptor (PR) and FKBP51, a protein inhibiting PR activity and linked to stress disorders.
• Previous research indicated elevated FKBP51 in iPTB and that Fkbp5 deficiency protects against stress-induced PTB.

Purpose of the Study:

• To investigate FKBP51 as a therapeutic target for preventing PTB.
• To evaluate the efficacy of 15-delta-prostaglandin J2 (15dPGJ2) in reducing FKBP51 levels and preventing stress-induced PTB.

Main Methods:

• Assessed FKBP51 levels and FKBP51-PR interactions in cultured cells and uterine tissues.
• Utilized a mouse model of stress-induced PTB.
• Administered 15dPGJ2 alone and in combination with progestins (P4 or R5020) to pregnant mice subjected to stress.

Main Results:

• 15dPGJ2 reduced FKBP51 levels and FKBP51-PR interactions in vitro.
• Maternal stress increased uterine Fkbp5, Oxtr, and Akr1c18 expression, shortening gestation.
• 15dPGJ2 treatment lowered uterine Fkbp51, Oxtr, and Ptgs2 levels and prevented stress-induced PTB.
• Combined 15dPGJ2 and progestin treatment showed the most significant protective effects.

Conclusions:

• FKBP51 inhibition represents a potential therapeutic strategy for preventing PTB.
• 15dPGJ2, alone or with progestins, demonstrates promise in preventing stress-induced PTB.
• Targeting FKBP51 may offer a novel approach to managing PTB.