Activation of farnesoid X receptor signaling by geniposidic acid promotes osteogenesis

Meijing Liu; Fujun Jin; Shuai Zhang; Shuang Li; Danqi Zhu; Yi Cui; Mingxiang Cai; Xiangning Liu; Yongbiao Zhang; Yao Sun; Changhui Liu; Xiaogang Wang

doi:10.1016/j.phymed.2022.154258

Activation of farnesoid X receptor signaling by geniposidic acid promotes osteogenesis

Phytomedicine. 2022 Aug:103:154258. doi: 10.1016/j.phymed.2022.154258. Epub 2022 Jun 9.

Authors

Meijing Liu¹, Fujun Jin², Shuai Zhang³, Shuang Li², Danqi Zhu², Yi Cui², Mingxiang Cai⁴, Xiangning Liu⁴, Yongbiao Zhang², Yao Sun⁵, Changhui Liu⁶, Xiaogang Wang⁷

Affiliations

¹ Key Laboratory of Big Data-Based Precision Medicine, School of Engineering Medicine, Beihang University, Beijing, 100191, China; Clinical Research Platform for Interdiscipline of Stomatology, The First Affiliated Hospital of Jinan University & Department of Stomatology, Jinan University, Guangzhou, 510632, China; School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
² Key Laboratory of Big Data-Based Precision Medicine, School of Engineering Medicine, Beihang University, Beijing, 100191, China.
³ Department of Oral Implantology, School of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, 200072, China.
⁴ Clinical Research Platform for Interdiscipline of Stomatology, The First Affiliated Hospital of Jinan University & Department of Stomatology, Jinan University, Guangzhou, 510632, China.
⁵ Department of Oral Implantology, School of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, 200072, China. Electronic address: yaosun@tongji.edu.cn.
⁶ School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.. Electronic address: liuchanghui@gzucm.edu.cn.
⁷ Key Laboratory of Big Data-Based Precision Medicine, School of Engineering Medicine, Beihang University, Beijing, 100191, China; Clinical Research Platform for Interdiscipline of Stomatology, The First Affiliated Hospital of Jinan University & Department of Stomatology, Jinan University, Guangzhou, 510632, China. Electronic address: xiaogangwang@buaa.edu.cn.

PMID: 35716540
DOI: 10.1016/j.phymed.2022.154258

Abstract

Background: New targets and strategies are urgently needed for the identification and development of anabolic drugs for osteoporosis. Farnesoid X receptor (FXR) is a promising novel therapeutic target for bone metabolism diseases. Although used clinically, FXR agonists have obvious side effects; therefore, the development of new FXR agonists for the treatment of osteoporosis would be welcomed. Geniposidic acid (GPA) is a bioactive compound extracted from Eucommiae cortex, which is used for treating arthritis, osteoporotic fractures, and hypertension. However, the therapeutic effects of GPA against osteoporosis remain underexplored.

Purpose: This study aims to reveal the potential osteogenic effects of FXR and to explore the effect of GPA on bone formation, osteoporosis treatment, and FXR signaling.

Study design & methods: The role of FXR in promoting bone formation was evaluated in Fxr knockout (Fxr^-/-) mice and cell models. GPA activation of FXR was evaluated by molecular docking and luciferase reporter gene assays. Thirty female C57BL/6J mice were randomly assigned into a sham operation group (Sham) and four ovariectomized (OVX) groups (n=6 each) and were treated with vehicle or different doses of GPA (25, 50, and 100 mg/kg/day). The therapeutic effect of GPA on osteoporosis was systematically analyzed by performing bone histomorphometry and measuring serum biochemical parameters, and the molecular mechanism was also evaluated. Furthermore, the action of GPA in Fxr^-/- mice was evaluated to investigate its dependency on FXR in promoting bone formation and treating osteoporosis.

Results: We found that FXR was highly expressed in bone tissues and enriched in osteoblasts. Notably, deletion of FXR significantly reduced the bone formation rate and bone mass of the Fxr^-/- mice compared with wild-type mice. Furthermore, using a high throughput drug screening strategy based on fluorescent reporter genes, we found that GPA functions as a natural agonist of FXR. We confirmed the activities of GPA on FXR activation and osteogenesis in both osteoblast differentiation models and OVX-induced osteoporosis models. We revealed that GPA strongly promotes bone formation by activating FXR/RUNX2 signaling. Moreover, the osteoporotic therapeutic effect of GPA was abolished in Fxr^-/- mice.

Conclusion: This study demonstrated that FXR is a promising target for treating osteoporosis and that GPA promotes bone formation in OVX-induced osteoporosis by activating FXR signaling. These findings provide novel insight into the mechanism by which GPA promotes bone formation and more evidence for its application in the treatment of osteoporosis.

Keywords: Bone formation; FXR; Geniposidic acid; Osteoporosis.

MeSH terms

Animals
Cell Differentiation
Female
Iridoid Glucosides* / pharmacology
Mice
Mice, Inbred C57BL
Mice, Knockout
Molecular Docking Simulation
Osteoblasts
Osteogenesis*
Osteoporosis* / drug therapy
Osteoporosis* / metabolism
Ovariectomy
Receptors, Cytoplasmic and Nuclear* / metabolism

Substances

Iridoid Glucosides
Receptors, Cytoplasmic and Nuclear
farnesoid X-activated receptor
geniposidic acid