Dihydroartemisinin, an Anti-Malaria Drug, Suppresses Estrogen Deficiency-Induced Osteoporosis, Osteoclast Formation, and RANKL-Induced Signaling Pathways

Zhou, Lin; Liu, Qian; Yang, Mingli; Wang, Tao; Yao, Jun; Cheng, Jian‐Wen; Yuan, Jinbo; Lin, Xiaofeng; Zhao, Jinmin; Tickner, Jennifer; Xu, Jiake

doi:10.1002/jbmr.2771

Cited by 91 publications

(103 citation statements)

References 49 publications

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“…However, TNF-α increased p65 expression and stimulated its nuclear translocation by inducing degradation of IκB-α which combined with p65 in the cytoplasm, reflecting the activation of the NF-κB pathway in chondrocytes. Consistent with results found in other cancer cells, fibroblast-like synoviocytes, and osteoclasts, DHA inhibited p65 nuclear translocation and reduced IκB-α degradation, suggesting that DHA inhibites the NF-κB pathway by modulating the IκB-α protein62024. Although the inhibitory role of DHA on NF-κB has been extensively studied, the association between NF-κB and autophagy in chondrocytes is unclear.…”

Section: Discussionsupporting

confidence: 80%

“…Treatment with 40 μM artesunate (a derivative of artemisinin) after 24 hours failed to reduce the viability of fibroblast-like synoviocytes24. Similarly, exposure to 0.5, 1, and 2.5 μM DHA after 48 hours demonstrated no cytotoxicity on bone marrow macrophages in mice6. In the present study, exposure to DHA levels 2.5 μM and greater after 48 and 72 hours inhibited cell proliferation, Whereas concentrations of 1 μM DHA or less had no inhibitory effect on chondrocytes.…”

Section: Discussionmentioning

confidence: 37%

“…Dihydroartemisinin (DHA), a semisynthetic derivative of ART and a novel anti-malarial agent, has fewer side effects than ART5. The biological activity of DHA in addition to its anti-malarial role suggests that it inhibits growth of cancer cells, suppresses estrogen deficiency-induced osteoporosis and osteoblast remodeling, and inhibits tumor angiogenesis67. The inhibitory role of DHA on inflammation- and catabolism-associated genes has also been reported89.…”

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confidence: 99%

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Dihydroartemisinin inhibits catabolism in rat chondrocytes by activating autophagy via inhibition of the NF-κB pathway

Jiang

Meng

Lee

et al. 2016

Sci Rep

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Osteoarthritis is a disease with inflammatory and catabolic imbalance in cartilage. Dihydroartemisinin (DHA), a natural and safe anti-malarial agent, has been reported to inhibit inflammation, but its effects on chondrocytes have yet to be elucidated. We investigated the effects of DHA on catabolism in chondrocytes. Viability of SD rats chondrocytes was analyzed. Autophagy levels were determined via expression of autophagic markers LC3 and ATG5, GFP-LC3 analysis, acridine orange staining, and electron microscopy. ATG5 siRNA induced autophagic inhibition. Catabolic gene and chemokine expression was evaluated using qPCR. The NF-κB inhibitor SM7368 and p65 over-expression were used to analyze the role of NF-κB pathway in autophagic activation. A concentration of 1 μM DHA without cytotoxicity increased LC3-II and ATG5 levels as well as autophagosomal numbers in chondrocytes. DHA inhibited TNF-α-induced expression of MMP-3 and -9, ADAMTS5, CCL-2 and -5, and CXCL1, which was reversed by autophagic inhibition. TNF-α-stimulated nuclear translocation and degradation of the p65 and IκBα proteins, respectively, were attenuated in DHA-treated chondrocytes. NF-κB inhibition activated autophagy in TNF-α-treated chondrocytes, but p65 over-expression reduced the autophagic response to DHA. These results indicate that DHA might suppress the levels of catabolic and inflammatory factors in chondrocytes by promoting autophagy via NF-κB pathway inhibition.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 37%

mentioning

confidence: 99%

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Dihydroartemisinin inhibits catabolism in rat chondrocytes by activating autophagy via inhibition of the NF-κB pathway

Jiang

Meng

Lee

et al. 2016

Sci Rep

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“…Each group contained five mice. A sham operation was conducted in the sham group as a control, whereas those in the other three groups underwent an ovariectomy (Zhou et al, 2016). The animals were maintained under standard animal housing conditions (12 h light/dark cycles and free access to food and water).…”

Section: Methodsmentioning

confidence: 99%

“…Oxidative stress stimuli transmitted by increased intracellular production of ROS could play as the secondary messengers in RANKL-induced osteoclast signaling pathways (Lee et al, 2005). By regulating these early signaling cascades, NFATc1 induces the expression of various osteoclast-specific genes, such as Dc-stamp , Calcr , Nfatc1 and c-Fos (Zhai et al, 2014; Zhou et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

Sitagliptin, An Anti-diabetic Drug, Suppresses Estrogen Deficiency-Induced OsteoporosisIn Vivo and Inhibits RANKL-Induced Osteoclast Formation and Bone Resorption In Vitro

Xiao

Zhai

et al. 2017

Front. Pharmacol.

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Postmenopausal osteoporosis is a disease characterized by excessive osteoclastic bone resorption. Some anti-diabetic drugs were demonstrated for anti-osteoclastic bone-loss effects. The present study investigated the skeletal effects of chronic administration of sitagliptin, a dipeptidyl peptidase IV (DPP IV) inhibitor that is increasingly used for type 2 diabetes treatments, in an estrogen deficiency-induced osteoporosis and elucidated the associated mechanisms. This study indicated that sitagliptin effectively prevented ovariectomy-induced bone loss and reduced osteoclast numbers in vivo. It was also indicated that sitagliptin suppressed receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclast differentiation, bone resorption, and F-actin ring formation in a manner of dose-dependence. In addition, sitagliptin significantly reduced the expression of osteoclast-specific markers in mouse bone-marrow-derived macrophages, including calcitonin receptor (Calcr), dendrite cell-specific transmembrane protein (Dc-stamp), c-Fos, and nuclear factor of activated T-cells cytoplasmic 1 (Nfatc1). Further study indicated that sitagliptin inhibited osteoclastogenesis by suppressing AKT and ERK signaling pathways, scavenging ROS activity, and suppressing the Ca2+ oscillation that consequently affects the expression and/or activity of the osteoclast-specific transcription factors, c-Fos and NFATc1. Collectively, these findings suggest that sitagliptin possesses beneficial effects on bone and the suppression of osteoclast number implies that the effect is exerted directly on osteoclastogenesis.

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Prussian Blue Nanozyme Normalizes Microenvironment to Delay Osteoporosis

Zhang

Zhao

et al. 2022

Adv Healthcare Materials

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Osteoporosis (OP) is the most common orthopedic disease in the elderly and the main cause of age‐related mortality and disability. However, no satisfactory intervention is currently available in clinical practice. Thus, an effective therapy to prevent or delay the development of OP should be devised. Osteoclastogenesis overactivation and excessive bone resorption are the main characteristics of OP. Accordingly, a paradigm for nanozyme‐mediated normalization of the disease microenvironment to regulate osteoclast differentiation and delay OP is proposed. Hollow Prussian blue nanozymes (HPBZs) are prepared via template‐free hydrothermal synthesis and selected as representative nanozymes. The intrinsic osteoclast activity‐remodeling bioactivities of the HPBZs are explored in vitro and in vivo, focusing on their impact on osteogenesis and specific molecular mechanisms using an OP murine model. The HPBZs significantly normalize the OP microenvironment, thereby inhibiting osteoclast formation and osteoclast resorption, possibly owing to the suppression of intracellular reactive oxygen species generation, the mitogen‐activated protein kinase, and nuclear factor κB signaling pathways. Consistently, in an ovariectomy‐induced OP murine model, HPBZ treatment significantly attenuates osteoporotic bone loss in vivo. The findings confirm the HPBZ‐mediated normalization of the disease microenvironment for the treatment of OP and suggest its application to other inflammation‐related diseases.

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Dihydroartemisinin, an Anti-Malaria Drug, Suppresses Estrogen Deficiency-Induced Osteoporosis, Osteoclast Formation, and RANKL-Induced Signaling Pathways

Cited by 91 publications

References 49 publications

Dihydroartemisinin inhibits catabolism in rat chondrocytes by activating autophagy via inhibition of the NF-κB pathway

Dihydroartemisinin inhibits catabolism in rat chondrocytes by activating autophagy via inhibition of the NF-κB pathway

Sitagliptin, An Anti-diabetic Drug, Suppresses Estrogen Deficiency-Induced OsteoporosisIn Vivo and Inhibits RANKL-Induced Osteoclast Formation and Bone Resorption In Vitro

Prussian Blue Nanozyme Normalizes Microenvironment to Delay Osteoporosis

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