2. Academic Validation
  3. Neuro-skeletal crosstalk: Brain-derived 5-HT mediates the bone-protective effects of β-Sitosterol against postmenopausal osteoporosis

Neuro-skeletal crosstalk: Brain-derived 5-HT mediates the bone-protective effects of β-Sitosterol against postmenopausal osteoporosis

  • Phytomedicine. 2025 Sep 9:148:157248. doi: 10.1016/j.phymed.2025.157248.
Kaixuan Wang 1,  Lining Wang 2,  Shijie Zhou 3,  Xi Chen 4,  Lihui Qian 5,  Tianchi Zhang 3,  Xiaoxian Sun 3,  Muzhe Li 3,  Mengmin Liu 1,  Yang Guo 6,  Yue Hu 7,  Yong Ma 8
Affiliations

Affiliations

  • 1 School of Integrative Medicine, Nanjing University of Chinese Medicine, No. 138, Xianlin Road, Qixia District, Nanjing City, Jiangsu 210023, China; Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China.
  • 2 School of Integrative Medicine, Nanjing University of Chinese Medicine, No. 138, Xianlin Road, Qixia District, Nanjing City, Jiangsu 210023, China; Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China; Jiangsu CM Clinical Innovation Center of Degenerative Bone & Joint Disease, Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine, China; Department of Orthopedics and Traumatology , Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, Jiangsu Province, China.
  • 3 Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China.
  • 4 Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China; School of Chinese Medicine, Nanjing University of Chinese Medicine, No. 138, Xianlin Road, Qixia District, Nanjing City, Jiangsu 210023, China.
  • 5 School of Medicine, Nanjing University of Chinese Medicine, 210023, Nanjing, China.
  • 6 Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China; Jiangsu CM Clinical Innovation Center of Degenerative Bone & Joint Disease, Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine, China. Electronic address: drguoyang@njucm.edu.cn.
  • 7 School of Integrative Medicine, Nanjing University of Chinese Medicine, No. 138, Xianlin Road, Qixia District, Nanjing City, Jiangsu 210023, China. Electronic address: yuehu@njucm.edu.cn.
  • 8 School of Integrative Medicine, Nanjing University of Chinese Medicine, No. 138, Xianlin Road, Qixia District, Nanjing City, Jiangsu 210023, China; Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China; Yancheng TCM Hospital Affiliated to Nanjing University of Chinese Medicine, 224000, Yancheng, Jiangsu Province, China. Electronic address: mayong@njucm.edu.cn.
PMID: 40961541 DOI: 10.1016/j.phymed.2025.157248
Abstract

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.

Keywords

5-HT; Postmenopausal osteoporosis; Sympathetic nerve; β -sitosterol.

Figures
Products