Diosgenin activates ERα-dependent PI3K/AKT/GSK3β signaling to enhance brain-derived serotonin and alleviate...

Postmenopausal osteoporosis (PMOP) stems from estrogen deficiency, which leads to reduced central serotonin (5-HT) levels, induces depressive-like behaviors, enhances sympathetic nervous system (SNS) activity, and disrupts bone homeostasis. However, the underlying mechanisms and potential therapeutic strategies targeting this pathway remain incompletely understood.

To test whether phytoestrogens diosgenin (DG) can inhibit bone loss in PMOP by restoring the 5-HT-SNS-bone metabolism circuit.

Ovariectomized (OVX) mice and a pharmacological 5-HT-depletion model were used to quantify the DG's impact on brain 5-HT synthesis, SNS output, and skeletal integrity. PC12 cells were probed to determine whether DG activation of estrogen receptor-alpha (ERα) and its downstream PI3K/AKT/GSK3β cascade regulated the 5-HT synthase tryptophan hydroxylase-2 (TPH2) and the catabolic enzyme monoamine oxidase A (MAOA).

DG triggers activation of PI3K/AKT/GSK3β via binding to membrane ERα, leading to increased central 5-HT levels, reduced SNS hyperactivity, and preservation of bone mass in OVX mice. In vitro, DG increased neuronal 5-HT supply by upregulating TPH2 and downregulating MAOA, mediated through the ERα-PI3K/AKT/GSK3β pathway.

DG stabilizes the 5-HT-SNS-bone formation loop by repairing estrogen deficiency-induced 5-HT reduction, thereby preventing bone loss in PMOP. These findings highlight DG as a promising therapeutic candidate for mitigating central 5-HT deficiency and protecting skeletal health in postmenopausal women.