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

Abstract

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 dosedependent 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.

Prevention and treatment of osteoporosis with natural products: Regulatory mechanism based on cell ferroptosis

“…Artesunate can induce ferroptosis in osteoclasts by increasing the production of malondialdehyde and 4-hydroxynonanal. This study also confirms that Artesunate plays a role in inhibiting the proliferation and differentiation of osteoclasts, reducing bone loss [ 117 ].…”

“…The activation of ARS by iron and the high iron content in osteoclasts may activate the ARS peroxide group to produce a large number of free radicals, thereby inhibiting the generation and bone resorption of osteoclasts [ 86 ]. In addition, it can also cause ferroptosis in OCs by downregulating the RANKL-induced osteoclastogenesis pathway [ 86 , 87 ].…”

Programmed cell death of periodontal ligament cells

“…Knockdown of transferrin receptor‐1 mitigated these cytotoxic effects of artemisinin on osteoclasts. These findings indicate that artemisinin and related compounds alleviate bone loss by inducing ferroptosis in osteoclasts (Jin et al, 2023) (Figure 5).…”

Type 2 diabetic mellitus related osteoporosis: focusing on ferroptosis

“…Owing to OCs’ iron-dependent nature of OCs, which is similar to that of cancer cells, they are more prone to iron-triggered ferroptosis. Research findings indicate that the artemisinin compound ART enhances the generation of MDA and 4-HNE, resulting in the manifestation of mitochondrial ferroptosis traits and prompting ferroptosis in OCs, which hinders their differentiation [ 191 ]. OCs differentiation increases under high glucose conditions, thereby enhancing the bone resorption capacity.…”