# C/EBPβ dictates postmenopausal FSHβ transcription and blockade of AEP/C/EBPβ pathway alleviates osteoporosis

## TL;DR

This study shows that C/EBPβ controls FSHβ production in the pituitary gland and blocking the AEP/C/EBPβ pathway can treat osteoporosis in postmenopausal women.

## Contribution

The study reveals C/EBPβ as a transcription factor for FSHβ and demonstrates that inhibiting AEP/C/EBPβ pathway can alleviate osteoporosis.

## Key findings

- C/EBPβ directly binds to and regulates the fshb gene promoter in the pituitary gland.
- Inhibiting AEP or knocking out C/EBPβ reduces FSHβ levels and prevents osteoporosis in mice.
- An AEP inhibitor (#11a) performs as well as teriparatide in treating OVX-induced osteoporosis.

## Abstract

Follicle-stimulating hormone (FSH), a gonadotropin that rises in post-menopausal females, activates its receptor FSHR to trigger bone loss via increasing bone resorption by osteoclasts. FSH stimulates CCAAT/enhancer binding protein beta (C/EBPβ) /asparagine endopeptidase (AEP) pathway, facilitating neural degeneration in the brain of mouse models with Alzheimer’s disease (AD). However, whether C/EBPβ/AEP pathway feeds back and modulates FSHβ bone resorption action remains elusive. Here we show that C/EBPβ acts as a transcription factor for fshb gene and directly binds its promoter, mediating its mRNA transcription in the pituitary gland. Knocking down C/EBPβ in primary pituitary cells significantly blunts GnRH (gonadotropin-releasing hormone)-induced FSHβ expression. Knockout of C/EBPβ also robustly diminishes FSHβ levels in mice. Inactivation of AEP, either by knockout of AEP or its small molecular inhibitor, antagonizes C/EBPβ and suppresses FSHβ levels, attenuating ovariectomy (OVX)-elicited osteoporosis. Markedly, a specific AEP inhibitor (#11a) displays comparable therapeutic effect as an FDA-approved drug teriparatide in OVX-induced osteoporosis. Hence, these findings support that C/EBPβ dictates FSHβ transcription and blocking AEP by its inhibitor represses C/EBPβ-mediated FSHβ levels, exerting prominent therapeutic efficacy toward osteoporosis.