TY - JOUR
T1 - Neuro-skeletal crosstalk
T2 - brain-derived 5-HT mediates the bone-protective effects of β-Sitosterol against postmenopausal osteoporosis
AU - Wang, Kaixuan
AU - Wang, Lining
AU - Zhou, Shijie
AU - Chen, Xi
AU - Qian, Lihui
AU - Zhang, Tianchi
AU - Sun, Xiaoxian
AU - Li, Muzhe
AU - Liu, Mengmin
AU - Guo, Yang
AU - Hu, Yue
AU - Ma, Yong
PY - 2025/11/25
Y1 - 2025/11/25
N2 - Background: Postmenopausal osteoporosis (PMOP) is frequently accompanied by depression, and the underlying neuro-skeletal crosstalk remains unclear. Serotonin and sympathetic nervous system (SNS) activity are implicated in both mood and bone regulation. Objective: To investigate whether β-sitosterol (βS) alleviates PMOP-associated depression and bone loss through modulation of central 5-hydroxytryptamine (5-HT) synthesis and SNS activity. Design: An integration of in vivo and in vitro studies using mouse models and cellular assays. Methods: Ovariectomized (OVX) and 5-HT-deficient mice were treated with βS. Behavioral assessments, micro-CT, immunohistochemistry, enzyme-linked immunosorbent assays (ELISA), Western blotting (WB), and molecular docking were employed to evaluate antidepressant effects, bone parameters, and related signaling pathways. In vitro, βS effects on 5-HT production and osteogenesis were assessed in PC12 cells and BMSCs. Results: βS enhanced brain 5-HT synthesis by activating the SIRT1/NRF2/TPH2 pathway and suppressing MAO-A. It alleviated depressive-like behaviors, reduced SNS activity, and prevented bone loss in both OVX and 5-HT-deficient mice. In vitro, βS increased 5-HT secretion in PC12 cells and promoted osteogenic differentiation in BMSCs via conditioned media. Conclusion: βS restores neuro-skeletal homeostasis by boosting 5-HT-mediated suppression of SNS activity, thereby improving mood and bone health. These findings identify βS as a promising candidate for treating comorbid PMOP and depression. Our study provides the first evidence linking phytosterol therapy to neuro-skeletal regulation in bone loss.
AB - Background: Postmenopausal osteoporosis (PMOP) is frequently accompanied by depression, and the underlying neuro-skeletal crosstalk remains unclear. Serotonin and sympathetic nervous system (SNS) activity are implicated in both mood and bone regulation. Objective: To investigate whether β-sitosterol (βS) alleviates PMOP-associated depression and bone loss through modulation of central 5-hydroxytryptamine (5-HT) synthesis and SNS activity. Design: An integration of in vivo and in vitro studies using mouse models and cellular assays. Methods: Ovariectomized (OVX) and 5-HT-deficient mice were treated with βS. Behavioral assessments, micro-CT, immunohistochemistry, enzyme-linked immunosorbent assays (ELISA), Western blotting (WB), and molecular docking were employed to evaluate antidepressant effects, bone parameters, and related signaling pathways. In vitro, βS effects on 5-HT production and osteogenesis were assessed in PC12 cells and BMSCs. Results: βS enhanced brain 5-HT synthesis by activating the SIRT1/NRF2/TPH2 pathway and suppressing MAO-A. It alleviated depressive-like behaviors, reduced SNS activity, and prevented bone loss in both OVX and 5-HT-deficient mice. In vitro, βS increased 5-HT secretion in PC12 cells and promoted osteogenic differentiation in BMSCs via conditioned media. Conclusion: βS restores neuro-skeletal homeostasis by boosting 5-HT-mediated suppression of SNS activity, thereby improving mood and bone health. These findings identify βS as a promising candidate for treating comorbid PMOP and depression. Our study provides the first evidence linking phytosterol therapy to neuro-skeletal regulation in bone loss.
KW - 5-HT
KW - Postmenopausal osteoporosis
KW - Sympathetic nerve
KW - β -sitosterol
UR - http://www.scopus.com/inward/record.url?scp=105015866122&partnerID=8YFLogxK
UR - https://go.openathens.net/redirector/westernsydney.edu.au?url=https://doi.org/10.1016/j.phymed.2025.157248
U2 - 10.1016/j.phymed.2025.157248
DO - 10.1016/j.phymed.2025.157248
M3 - Article
AN - SCOPUS:105015866122
SN - 0944-7113
VL - 148
JO - Phytomedicine
JF - Phytomedicine
M1 - 157248
ER -