Artesunate inhibits osteoclast differentiation by inducing ferroptosis and prevents iron overload‐induced bone loss

Artemisinin compounds have been demonstrated to have anti‐osteoporosis effects by inhibiting bone resorption. During osteoclast differentiation, osteoclasts take up a large amount of iron through transferrin receptor 1 (TfR1) mediated endocytosis of transferrin (Tf). Since iron‐dependent cleavage of...

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Published in:Basic & clinical pharmacology & toxicology 2023-02, Vol.132 (2), p.144-153
Main Authors: Jin, Yuanqing, Wu, Shuguang, Zhang, Lingyan, Yao, Gang, Zhao, Hai, Qiao, Penghai, Zhang, Jian
Format: Article
Language:English
Subjects:
Artemisinin
Artesunate
Bone loss
Bone resorption
Cytotoxicity
Differentiation
Endocytosis
Ferroptosis
Iron
Mitochondria
Osteoclastogenesis
Osteoclasts
Osteoporosis
Overloading
Transferrin
Transferrins
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Summary:Artemisinin compounds have been demonstrated to have anti‐osteoporosis effects by inhibiting bone resorption. During osteoclast differentiation, osteoclasts take up a large amount of iron through transferrin receptor 1 (TfR1) mediated endocytosis of transferrin (Tf). Since iron‐dependent cleavage of endoperoxide bridge is of great importance for the antimalarial effects of artemisinin compounds, we raised a hypothesis that the cytotoxic effects of artemisinin compounds on osteoclasts were associated with enhanced iron uptake. In the present study, we found that Tf aggravated the inhibitory effects of artesunate (ART) on osteoclast viability and differentiation. ART induced the production of malondialdehyde (MDA) and 4‐hydroxynonenal (4‐HNE) in a dose‐dependent manner and led to the appearance of mitochondrial features of ferroptotic cells. TfR1 knockdown alleviated these cytotoxic effects of ART on osteoclasts. In addition, ART effectively prevented bone loss induced by iron overload. Our results indicate that ART inhibits iron‐uptake stimulated osteoclast differentiation by inducing ferroptosis. Artemisinin compounds are potential drugs for treating iron overload‐induced osteoporosis.
ISSN:1742-7835
1742-7843
DOI:10.1111/bcpt.13817