Ellagic acid inhibits CDK12 to increase osteoblast differentiation and alleviate osteoporosis in hindlimb-unloaded and ovariectomized mice

Zixiang Wu; Lifang Hu; Kang Ru; Wenjuan Zhang; Xia Xu; Shuyu Liu; Hua Liu; Yunxia Jia; Shujing Liang; Zhihao Chen; Airong Qian

doi:10.1016/j.phymed.2023.154745

Ellagic acid inhibits CDK12 to increase osteoblast differentiation and alleviate osteoporosis in hindlimb-unloaded and ovariectomized mice

Phytomedicine. 2023 Jun:114:154745. doi: 10.1016/j.phymed.2023.154745. Epub 2023 Mar 6.

Authors

Zixiang Wu¹, Lifang Hu², Kang Ru¹, Wenjuan Zhang¹, Xia Xu¹, Shuyu Liu¹, Hua Liu¹, Yunxia Jia¹, Shujing Liang¹, Zhihao Chen¹, Airong Qian³

Affiliations

¹ Lab for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, China; Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, China; Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, China; NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, China.
² Lab for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, China; Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, China; Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, China; NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, China. Electronic address: hulifang@nwpu.edu.cn.
³ Lab for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, China; Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, China; Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, China; NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, China. Electronic address: qianair@nwpu.edu.cn.

PMID: 36931096
DOI: 10.1016/j.phymed.2023.154745

Abstract

Background: Osteoporosis is a highly prevalent bone disease occurred commonly in astronauts and postmenopausal women due to mechanical unloading and estrogen deficiency, respectively. At present, there are some traditional Chinese medicine compounds for preventing and treating osteoporosis induced by simulated microgravity, but the detailed components of the traditional Chinese medicines still need to be confirmed and osteoporosis is still untreatable due to a lack of effective small-molecule natural medicine.

Purpose: To explore the role of cyclin-dependent kinase 12 (CDK12) in osteoporosis induced by simulated microgravity and the therapeutic effect of CDK12-targeted Ellagic Acid (EA) on osteoporosis.

Methods: Our previous study has suggested that CDK12 as a potential target for treating and preventing osteoporosis. In this study, the role of CDK12 in osteoblasts and mice bone tissues was further studied under simulated microgravity. And by targeting CDK12, natural small-molecule product EA was screened out based on a large scale through the weighted set similarity (WES) method and the therapeutic effects of EA on osteoporosis was investigated in hindlimb-unloaded (HU) mouse model and ovariectomized (OVX) model.

Results: The results demonstrated that simulated microgravity inhibited bone formation and up-regulated the expression of CDK12. Furthermore, CDK12-siRNA or THZ531 (an inhibitor of CDK 12) promoted osteoblast differentiation, while the overexpression of CDK12 inhibited osteoblasts differentiation. And we further proved that CDK12-targeted EA showed a rescue effect on osteoblast differentiation inhibition caused by simulated microgravity. EA (50 mg·kg^-1·day^-1) daily intragastric administration alleviated the symptoms of osteoporosis and accompanied with the improvement of trabecular bone and cortical bone parameters with significantly overexpression of CDK12.

Conclusion: EA efficiently improves osteoporosis by targeting CDK12, which is a suppresser of osteoblast differentiation and a novel therapeutic target for treating osteoporosis.

Keywords: CDK12; Ellagic acid; Hindlimb-unloaded; Osteoblast differentiation; Ovariectomized; Simulated microgravity.

MeSH terms

Animals
Cell Differentiation
Cyclin-Dependent Kinases / metabolism
Cyclin-Dependent Kinases / pharmacology
Ellagic Acid / pharmacology
Female
Hindlimb
Mice
Osteoblasts / metabolism
Osteogenesis*
Osteoporosis* / metabolism

Substances

Ellagic Acid
Cyclin-Dependent Kinases