Obacunone targets macrophage migration inhibitory factor (MIF) to impede osteoclastogenesis and alleviate ovariectomy-induced bone loss

作者：He, Jianbo; Zheng, Lin; Li, Xiaojuan; Huang, Furong; Hu, Sitao; Chen, Lei; Jiang, Manya; Lin, Xianfeng; Jiang, Haibo; Zeng, Yifan; Ye, Tianshen; Lin, Dingkun; Liu, Qian^*; Xu, Jiake^*; Chen, Kai^*

来源：Journal of Advanced Research, 2023, 53: 235-248.

DOI：10.1016/j.jare.2023.01.003

• Obacunone
• Macrophage migration inhibitory factor
• (MIF)
• Osteoclast
• Reactive oxygen species (ROS)
• Bone loss

Introduction: Osteoporosis is the most common bone disorder where the hyperactive osteoclasts repre-sent the leading role during the pathogenesis. Targeting hyperactive osteoclasts is currently the primary therapeutic strategy. However, concerns about the long-term efficacy and side effects of current frontline treatments persist. Alternative therapeutic agents are still needed.Objectives: Obacunone (OB) is a small molecule with a broad spectrum of biological activities, particu-larly antioxidant and anti-inflammatory effects. This study aims to examine OB's therapeutic potential on osteoporosis and explore the rudimentary mechanisms. Methods: Osteoclast formation and osteoclastic resorption assays were carried out to examine OB's inhi-bitory effects in vitro, followed by the in-vivo studies of OB's therapeutic effects on ovariectomy-induced osteoporotic preclinical model. To further study the underlying mechanisms, mRNA sequencing and anal-ysis were used to investigate the changes of downstream pathways. The molecular targets of OB were predicted, and in-silico docking analysis was performed. Ligand-target binding was verified by surface plasmon resonance (SPR) assay and Western Blotting assay.Results: The results indicated that OB suppressed the formation of osteoclast and its resorptive function in vitro. Mechanistically, OB interacts with macrophage migration inhibitory factor (MIF) which attenu-ates receptor activator of nuclear factor kappa B (NF -KB) ligand (RANKL)-induced signaling pathways, including reactive oxygen species (ROS), NF -KB pathway, and mitogen-activated protein kinases (MAPKs). These effects eventually caused the diminished expression level of the master transcriptional factor of osteoclastogenesis, nuclear factor of activated T cells 1 (NFATc1), and its downstream osteoclast-specific proteins. Furthermore, our data revealed that OB alleviated estrogen deficiency -induced osteoporosis by targeting MIF and thus inhibiting hyperactive osteoclasts in vivo.Conclusion: These results together implicated that OB may represent as a therapeutic candidate for bone disorders caused by osteoclasts, such as osteop

• 单位
  浙江大学; 广州中医药大学; 广东省人民医院; jk