Chrysin Protects Against Titanium Particle-Induced Osteolysis by Attenuating Osteoclast Formation and Function by Inhibiting NF-κB and MAPK Signaling

Zuoxing Wu; Chen Li; Yu Chen; Qian Liu; Na Li; Xuemei He; Weibin Li; Rong Shen; Li Li; Chenming Wei; Siyuan Shao; Fangsheng Fu; Jiaxin Ding; Xiaochen Sun; Dairong Wang; Guixin Yuan; Yiji Su; Jinmin Zhao; Jiake Xu; Ren Xu; Xin Xu; Feng Xu

doi:10.3389/fphar.2022.793087

Chrysin Protects Against Titanium Particle-Induced Osteolysis by Attenuating Osteoclast Formation and Function by Inhibiting NF-κB and MAPK Signaling

Front Pharmacol. 2022 Mar 23:13:793087. doi: 10.3389/fphar.2022.793087. eCollection 2022.

Authors

Zuoxing Wu^{1

2}, Chen Li¹, Yu Chen², Qian Liu¹, Na Li², Xuemei He², Weibin Li³, Rong Shen², Li Li⁴, Chenming Wei¹, Siyuan Shao¹, Fangsheng Fu¹, Jiaxin Ding¹, Xiaochen Sun¹, Dairong Wang⁵, Guixin Yuan⁶, Yiji Su¹, Jinmin Zhao¹, Jiake Xu⁷, Ren Xu^{1

2

8}, Xin Xu¹, Feng Xu^{1

9}

Affiliations

¹ Research Centre for Regenerative Medicine, Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, China.
² Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, China.
³ Xiang'an Hospital, School of Medicine, Xiamen University, Xiamen, China.
⁴ Pharmaceutic College, Guangxi Medical University, Nanning, China.
⁵ Department of Orthopedics, Guilin People's Hospital, Guilin, China.
⁶ Department of Orthopedics, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China.
⁷ School of Biomedical Sciences, The University of Western Australia, Perth, WA, Australia.
⁸ Department of Orthopedic Surgery, The First Afiliated Hospital of Xiamen University, Xiamen, China.
⁹ Department of Subject Planning, Ninth Peoples Hospital Shanghai, Jiaotong University School of Medicine, Shanghai, China.

Abstract

Bone homeostasis only exists when the physical function of osteoblast and osteoclast stays in the balance between bone formation and resorption. Bone resorption occurs when the two processes are uncoupled, shifting the balance in favour of bone resorption. Excessive activation of osteoclasts leads to a range of osteolytic bone diseases including osteoporosis, aseptic prosthesis loosening, rheumatoid arthritis, and osteoarthritis. Receptor activator of nuclear factor kappa-B ligand (RANKL) and its downstream signaling pathways are recognized as key mediators that drive the formation and activation of osteoclastic function. Hence, osteoclast formation and/or its function remain as dominant targets for research and development of agents reaching the treatment towards osteolytic diseases. Chrysin (CHR) is a flavonoid with a wide range of anti-inflammatory and anti-tumor effects. However, its effect on osteoclasts remains unknown. In this study, we found the effects of CHR on inhibiting osteoclast differentiation which were assessed in terms of the number and size of TRAcP positive multinucleated osteoclasts (OCs). Further, the inhibitory effects of CHR on bone resorption and osteoclast fusion of pre-OC were assessed by hydroxyapatite resorption pit assay and F-actin belts staining; respectively. Western blotting analysis of RANKL-induced signaling pathways and immunofluorescence analysis for p65 nuclear translocation in response to RANKL-induced osteoclasts were used to analyze the mechanism of action of CHR affecting osteoclasts. Lastly, the murine calvarial osteolysis model revealed that CHR could protect against particle-induced bone destruction in vivo. Collectively, our data strongly suggested that CHR with its promising anti-tumor effects would also be a potential therapeutic agent for osteolytic diseases.

Keywords: MAPK; NF-κB; chrysin; osteoclast; osteolysis.