Integrated Strategy of Network Pharmacological Prediction and Experimental Validation Elucidate Possible Mechanism of Bu-Yang Herbs in Treating Postmenopausal Osteoporosis via ESR1

Hanting Xia; Jiangyuan Liu; Wenlong Yang; Min Liu; Yunfeng Luo; Zhijun Yang; Jingbo Xie; Huiliang Zeng; Rui Xu; Houfu Ling; Qinghe Zeng; Huihui Xu; Liang Fang; Hongyu Wang; Peijian Tong; Hongting Jin; Fengyun Yang

doi:10.3389/fphar.2021.654714

Integrated Strategy of Network Pharmacological Prediction and Experimental Validation Elucidate Possible Mechanism of Bu-Yang Herbs in Treating Postmenopausal Osteoporosis via ESR1

Front Pharmacol. 2021 May 11:12:654714. doi: 10.3389/fphar.2021.654714. eCollection 2021.

Authors

Hanting Xia^{1

2

3}, Jiangyuan Liu⁴, Wenlong Yang³, Min Liu³, Yunfeng Luo⁴, Zhijun Yang⁴, Jingbo Xie⁵, Huiliang Zeng⁶, Rui Xu^{1

2}, Houfu Ling^{1

2}, Qinghe Zeng^{1

2}, Huihui Xu^{1

2}, Liang Fang^{1

2}, Hongyu Wang⁴, Peijian Tong^{1

2

7}, Hongting Jin^{1

2

7}, Fengyun Yang⁴

Affiliations

¹ The First Clinical College, Zhejiang Chinese Medical University, Hangzhou, China.
² Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.
³ Department of Orthopedics, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, China.
⁴ Graduated School, Jiangxi University of Chinese Medicine, Nanchang, China.
⁵ Department of Orthopedics, People's Hospital of Fengcheng City, Fengcheng, China.
⁶ Department of Orthopedics, Foshan Hospital of Traditional Chinese Medicine, Foshan, China.
⁷ Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.

Abstract

Postmenopausal osteoporosis (PMOP) is a type of bone metabolism disease-related to estrogen deficiency with an increasing incidence. Traditional Chinese (TCM) has always been used and showed effectiveness in treating PMOP. In the current study, Bu-Yang herbs were considered to be the most frequently used and efficient TCM herbs in PMOP treatment. However, chemical and pharmacological profiles were not elucidated. Network pharmacology was conducted on representative Bu-Yang herbs (Yin-Yang-Huo. Du-Zhong, Bu-Gu-Zhi, Tu-Si-Zi) to investigate the mechanism of Bu-Yang herbs on PMOP. Chemical compounds, potential targets, and disease related genes were available from the corresponding database. Results showed that Bu-Yang herbs could interact with ESR1 and estrogen signaling pathways. For further validation, the Bu-Yang decoction (BYD), formula consisted of the above-mentioned 4 Bu-Yang herbs was presented for experimental validation. In vivo, BYD significantly reversed ovariectomy (OVX)-induced osteoporosis progress in a dose-dependent manner by up-regulation of bone mineral density and amelioration of bone microarchitecture. In vitro, BYD dramatically improved the proliferation and mineral nodules formation of osteoblasts. Both in vitro and in vivo results illustrated that the phenotype change induced by BYD is correlated with up-regulated of ESR1 and activation of the β-catenin pathway. Meanwhile, inhibition of ESR1 by ICI182, 780 blocked the osteogenic phenotype and β-catenin pathway activation induced by BYD. In conclusion, the current study suggested that Bu-Yang herbs are the most useful TCM herbs in treating PMOP. Furthermore, the integrated strategy of network pharmacology prediction with experimental validation suggested that BYD exerted its anti-PMOP via ESR1 and the downstream mechanism might be activation of the β-catenin signaling pathway.

Keywords: Bu-Yang; estrogen receptor; network pharmacology; postmenopausal osteoporosis; traditional Chinese medicine.