2. Academic Validation
  3. PPARγ-SMAD6 axis-mediated inhibition of osteogenic differentiation is involved in BPS-induced osteoporosis

PPARγ-SMAD6 axis-mediated inhibition of osteogenic differentiation is involved in BPS-induced osteoporosis

  • Environ Int. 2025 Apr:198:109442. doi: 10.1016/j.envint.2025.109442.
Zhenkun Weng 1,  Xiu Chen 2,  Jian Jiao 2,  Zuqiang Fu 2,  Qian Liu 2,  Jin Xu 2,  Hongchao Zhang 3,  Qingzhi Hou 4,  Dongmei Wang 5,  Jiong Li 2,  Shourui Wang 2,  Zhen Zhang 2,  Yanlong Chen 2,  Sining Meng 2,  Zhaoyan Jiang 3,  Aihua Gu 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Reproductive Medicine and Offspring Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Jiangsu Environmental Health Risk Assessment Engineering Research Center, Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, Nanjing Medical University, Nanjing 211166, China; Changzhou Second People's Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou 213004, China.
  • 2 State Key Laboratory of Reproductive Medicine and Offspring Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Jiangsu Environmental Health Risk Assessment Engineering Research Center, Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, Nanjing Medical University, Nanjing 211166, China.
  • 3 Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, Nanjing 211166, China.
  • 4 School of Public Health and Management, Shandong First Medical University, Jinan, Shandong 250117, China.
  • 5 Changzhou Second People's Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou 213004, China.
  • 6 State Key Laboratory of Reproductive Medicine and Offspring Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Jiangsu Environmental Health Risk Assessment Engineering Research Center, Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, Nanjing Medical University, Nanjing 211166, China. Electronic address: aihuagu@njmu.edu.cn.
PMID: 40215917 DOI: 10.1016/j.envint.2025.109442
Abstract

Bisphenol S (BPS) is extensively utilized in personal care products, foods, and paper products, raising growing concerns about its potential environmental hazards. However, few studies have reported the effects of BPS exposure on bone homeostasis. In this study, using data from the National Health and Nutrition Examination Survey, we found a negative correlation between urinary BPS and bone mineral density (BMD). To further investigate the underlying mechanisms, C57BL/6 mice were exposed to a human-equivalent dose of BPS for 6 months. Micro-CT analysis demonstrated reduced femoral BMD in the mice, indicating that osteoporosis was caused by chronic exposure. RNA-seq analysis showed that BPS activated PPARγ in human primary mesenchymal stem cells (MSCs). Additionally, 3D molecular docking confirmed a direct interaction between BPS and PPARγ. Bioinformatics analysis identified SMAD6 as a downstream target of PPARγ. Mechanistically, the BPS-PPARγ interaction activated PPARγ, promoting SMAD6 transcription, which inhibited the osteogenic differentiation of MSCs. High-throughput virtual screening further revealed that olodanrigan effectively blocked the BPS-PPARγ interaction, and in vitro assays revealed that olodanrigan blocked the inhibition of osteogenic differentiation of MSCs induced by BPS. Additionally, olodanrigan supplementation inhibited PPARγ levels, thereby reversing BPS-induced osteoporosis. In summary, this study elucidates the role of the PPARγ-SMAD6 axis in mediating BPS-induced osteoporosis and highlights olodanrigan as a promising therapeutic intervention, offering new insights into the health risks posed by BPS and potential targets for treatment.

Keywords

BPS; Osteogenic differentiation; Osteoporosis; PPARγ.

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