Journal of advanced research · 2025
Diosgenin activates ERα-dependent PI3K/AKT/GSK3β signaling to enhance brain-derived serotonin and alleviate postmenopausal bone loss.
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Chen Xi, Zhang MengXue, Qian Lihui, Guo Yang, Zhu Yihua, Taxi Wumiti, Liu Mengmin, Wang Kaixuan, Song Likun, Zhang Chunlei, Zhang Yafeng, Wang Lining, Ma Yong, Hu Yue
Аннотация
INTRODUCTION: 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.
OBJECTIVE: To test whether phytoestrogens diosgenin (DG) can inhibit bone loss in PMOP by restoring the 5-HT-SNS-bone metabolism circuit.
METHODS: 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).
RESULTS: 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.
CONCLUSION: 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.
OBJECTIVE: To test whether phytoestrogens diosgenin (DG) can inhibit bone loss in PMOP by restoring the 5-HT-SNS-bone metabolism circuit.
METHODS: 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).
RESULTS: 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.
CONCLUSION: 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.