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

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.