Betulinic Acid Protects From Bone Loss in Ovariectomized Mice and Suppresses RANKL-Associated Osteoclastogenesis by Inhibiting the MAPK and NFATc1 Pathways

Jiyong Wei; Yicheng Li; Qian Liu; Yanni Lan; Chengming Wei; Kun Tian; Liwei Wu; Chunbo Lin; Jiake Xu; Jinmin Zhao; Yuan Yang

doi:10.3389/fphar.2020.01025

Betulinic Acid Protects From Bone Loss in Ovariectomized Mice and Suppresses RANKL-Associated Osteoclastogenesis by Inhibiting the MAPK and NFATc1 Pathways

Front Pharmacol. 2020 Jul 7:11:1025. doi: 10.3389/fphar.2020.01025. eCollection 2020.

Authors

Jiyong Wei^{1

2

3

4}, Yicheng Li¹, Qian Liu^{1

5}, Yanni Lan⁶, Chengming Wei¹, Kun Tian^{1

2

3}, Liwei Wu^{1

2

3}, Chunbo Lin⁷, Jiake Xu^{1

5}, Jinmin Zhao^{1

2

3}, Yuan Yang^{1

2

7}

Affiliations

¹ Research Centre for Regenerative Medicine, Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, China.
² Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, China.
³ Department of Orthopaedics Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning, China.
⁴ Department of Orthopedics, The First People's Hospital of Nanning, Nanning, China.
⁵ School of Biomedical Sciences, The University of Western Australia, Perth, WA, Australia.
⁶ Department of Pharmacy, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
⁷ Orthopaedics, Langdong Hospital of Guangxi Medical University, Guangxi Medical University, Nanning, China.

Abstract

Osteoclasts with elevated bone resorption are commonly present in postmenopausal osteoporosis, and other osteolytic pathologies. Therefore, suppressing osteoclast generation and function has been the main focus of osteoporosis treatment. Betulinic acid (BA) represents a triterpenoid mainly purified from the bark of Betulaceae. BA shows multiple biological activities, including antitumor and anti-HIV properties, but its effect on osteolytic conditions is unknown. Here, BA suppressed receptor activator of nuclear factor-κB ligand (RANKL)-associated osteoclastogenesis and bone resorptive function, as assessed by tartrate-resistant acid phosphatase (TRAP) staining, fibrous actin ring generation, and hydroxyapatite resorption assays. Mechanistically, BA downregulated the expression of osteoclastic-specific genes. Western blot analysis revealed that BA significantly interrupted ERK, JNK and p38 MAPK activation as well as intracellular reactive oxygen species (ROS) production, thus altering c-Fos and NFATc1 activation. Corroborating the above findings in cell-based assays, BA prevented ovariectomy-associated bone loss in an animal model. In conclusion, these findings suggest that BA can inhibit osteoclast generation and function as well as the RANKL signaling pathway, and might be used for treating osteoclast-related osteoporosis.

Keywords: MAPK; betulinic acid; osteoclast; osteoporosis; receptor activator of nuclear factor‐κB ligand.