Damascenone inhibits osteoclastogenesis by epigenetically modulating Nrf2-mediated ROS scavenge and counteracts OVX-induced osteoporosis

Qingliang Ma; Yinuo Xiong; Zhiwei Jie; Changzhen Li; Congyu Wang; Jingwen Cai; Yuchen Zhang; Jinghang Li; Yunhao You; Mingzheng Chang; Dapeng Zhang; Cheng Qiu; Yuhua Li; Xinyu Liu; Lianlei Wang

doi:10.1016/j.phymed.2024.156205

Damascenone inhibits osteoclastogenesis by epigenetically modulating Nrf2-mediated ROS scavenge and counteracts OVX-induced osteoporosis

Phytomedicine. 2024 Nov 3:135:156205. doi: 10.1016/j.phymed.2024.156205. Online ahead of print.

Authors

Qingliang Ma¹, Yinuo Xiong², Zhiwei Jie³, Changzhen Li², Congyu Wang², Jingwen Cai⁴, Yuchen Zhang², Jinghang Li², Yunhao You¹, Mingzheng Chang¹, Dapeng Zhang¹, Cheng Qiu², Yuhua Li¹, Xinyu Liu⁵, Lianlei Wang⁶

Affiliations

¹ Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong, China.
² Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong, China; Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
³ Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁴ Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.
⁵ Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong, China; Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. Electronic address: [email protected].
⁶ Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong, China. Electronic address: [email protected].

PMID: 39547093
DOI: 10.1016/j.phymed.2024.156205

Abstract

Background: Bone formation and resorption regulate bone homeostasis. Excessive osteoclastogenesis enhances bone resorption and causes osteoporosis. Although medicines targeting osteoclast have been developed, these drugs have several side effects. Natural compounds have advantages in safety and efficiency, making them potential candidates for osteoporosis treatment.

Purpose: This study aims to elucidate the role of damascenone (Dama) in osteoclastogenesis and osteoporosis.

Study design and methods: To demonstrate the effect of Dama on osteoclast differentiation and function, we performed multiple in vitro experiments including TRAP staining, F-actin staining, bone slice resorption assay, real-time PCR, and western bolt. Further, ROS detection, network pharmacology, microscale thermophoresis assay, and ChIP assay were conducted to elucidate the underlying molecular mechanism. Finally, the in vivo effects of Dama were verified using an ovariectomy induced osteoporosis mice model.

Results: Dama inhibited RANKL-induced osteoclast differentiation and bone resorptive function in vitro. The expression of osteoclast-related genes and activation of MAPKs and NF-κB signaling in osteoclast were also attenuated by Dama. Meanwhile, Dama reduced intracellular ROS level via up-regulating Nrf2 expression. Network pharmacology demonstrated that HDAC2 is the potential direct target of Dama. Dama inhibited HDAC2 function and increased H3K27ac level of Nrf2, which induced Nrf2 expression and activated ROS scavenging enzymes. Inhibiting NRF2 or activating HDAC2 attenuated the effect of Dama on osteoclastogenesis. Finally, Dama injection suppressed in vivo osteoclastogenesis and ameliorated bone loss induced by OVX.

Conclusion: Dama attenuates osteoclastogenesis by epigenetically modulating Nrf2 expression and ROS scavenge. This study provides evidence for Dama being a potential treatment for osteoporosis.

Keywords: Damascenone; HDAC2; Nrf2; Osteoclast; Osteoporosis; ROS.