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Obacunone targets macrophage migration inhibitory factor (MIF) to impede osteoclastogenesis and alleviate
Jianbo He1, Lin Zheng2, Xiaojuan Li3
1Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou 510632, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, China; School of Biomedical Sciences, The University of Western Australia, Perth 6009, Australia.
Introduction:
Osteoporosis is the most common bone disorder where the hyperactive osteoclasts represent 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, particularly 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 inhibitory 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 analysis 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 attenuates receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL)-induced signaling pathways, including reactive oxygen species (ROS), NF-κB 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 osteoporosis.
Insights
Obacunone (OB) effectively inhibits osteoclast formation and function, offering a potential new treatment for osteoporosis. This compound targets macrophage migration inhibitory factor (MIF), reducing bone resorption and improving bone health.
Area of Science:
- Biochemistry
- Pharmacology
- Bone Biology
Background:
- Osteoporosis is a prevalent bone disorder driven by hyperactive osteoclasts.
- Current osteoporosis treatments face challenges with long-term efficacy and side effects.
- Novel therapeutic agents targeting osteoclasts are needed.
Purpose of the Study:
- To investigate the therapeutic potential of Obacunone (OB) in osteoporosis.
- To elucidate the underlying mechanisms of OB's action on osteoclasts.
Main Methods:
- In vitro osteoclast formation and resorption assays.
- In vivo studies using an ovariectomy-induced osteoporosis model.
- mRNA sequencing, in-silico docking, surface plasmon resonance (SPR), and Western Blotting assays.
Main Results:
- OB suppressed osteoclast formation and resorptive activity in vitro.
- OB targets macrophage migration inhibitory factor (MIF), attenuating RANKL-induced signaling pathways (ROS, NF-κB, MAPKs).
- OB reduced NFATc1 expression and alleviated osteoporosis in vivo by inhibiting hyperactive osteoclasts.
Conclusions:
- Obacunone (OB) demonstrates therapeutic potential for osteoporosis.
- OB acts by targeting MIF and inhibiting osteoclastogenesis.
- OB represents a promising candidate for treating osteoclast-related bone disorders.
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