Therapeutic potential of iron chelators on osteoporosis and their cellular mechanisms

Zhang, Jian; Zhao, Hai; Yao, Gang; Qiao, Penghai; Li, Longfei; Wu, Shaofang

doi:10.1016/j.biopha.2021.111380

Cited by 31 publications

(20 citation statements)

References 118 publications

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“…Osteoclasts also play an important role in osteoporosis and are affected by iron. Previous studies have shown that formation and differentiation of osteoclasts are associated with remarkable changes in cellular iron homeostasis 36–38 . A recent study showed that deletion of FPN in myeloid cells leads to iron accumulation and stimulates osteoclastogenic differentiation in mice 39 .…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that formation and differentiation of osteoclasts are associated with remarkable changes in cellular iron homeostasis. [36][37][38] A recent study showed that deletion of FPN in myeloid cells leads to iron accumulation and stimulates osteoclastogenic differentiation in mice. 39 Iron overload promotes differentiation of osteoclasts through induction of ROS.…”

Section: Discussionmentioning

confidence: 99%

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Iron overload‐induced ferroptosis of osteoblasts inhibits osteogenesis and promotes osteoporosis: An in vitro and in vivo study

Jiang

Wang

et al. 2022

IUBMB Life

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Growing evidence indicates that iron overload is an independent risk factor for osteoporosis. However, the mechanisms are not fully understood. The purpose of our study was to determine whether iron overload could lead to ferroptosis in osteoblasts and to explore whether ferroptosis of osteoblasts is involved in iron overload‐induced osteoporosis in vitro and in vivo. Ferric ammonium citrate was used to mimic iron overload conditions, while deferoxamine and ferrostatin‐1 were used to inhibit ferroptosis of MC3T3‐E1 cells in vitro. The ferroptosis, osteogenic differentiation and mineralization of MC3T3‐E1 cells were assessed in vitro. A mouse iron overload model was established using iron dextran. Immunohistochemical analysis was performed to determine ferroptosis of osteoblasts in vivo. Enzyme‐linked immunosorbent assays and calcein–alizarin red S labelling were used to assess new bone formation. Dual x‐ray absorptiometry, micro‐computed tomography and histopathological analysis were conducted to evaluate osteoporosis. The results showed that iron overload reduced cell viability, superoxide dismutase and glutathione levels, increased reactive oxygen species generation, lipid peroxidation, malondialdehyde levels and ferroptosis‐related protein expression, and induced ultrastructural changes in mitochondria. Iron overload could also inhibit osteogenic differentiation and mineralization in vitro. Inhibiting ferroptosis reversed the changes described above. Iron overload inhibited osteogenesis, promoted the ferroptosis of osteoblasts and induced osteoporosis in vivo, which could also be improved by deferoxamine and ferrostatin‐1. These results demonstrate that ferroptosis of osteoblasts plays a crucial role in iron overload‐induced osteoporosis. Maintaining iron homeostasis and targeting ferroptosis of osteoblasts might be potential measures of treating or preventing iron overload‐induced osteoporosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Iron overload‐induced ferroptosis of osteoblasts inhibits osteogenesis and promotes osteoporosis: An in vitro and in vivo study

Jiang

Wang

et al. 2022

IUBMB Life

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“…Subsequently, the ferrous iron enters the cytoplasm via divalent metal transporter 1 (DMT1) and is utilized for the synthesis of heme and iron-sulfur (Fe/S) clusters. The excess iron can be stored in ferritin, the major iron-storage protein at the cellular level, or is exported from cells through FPN1, the only known iron exporter ( Sacco et al, 2021 ; Zhang et al, 2021 ). Hepcidin, an iron regulator synthesized in the liver, controls iron export from cells by inducing the internalization and degradation of FPN1 ( Camaschella et al, 2020 ).…”

Section: Iron Oxidative Stress and Ferroptosismentioning

confidence: 99%

Nrf2 Is a Potential Modulator for Orchestrating Iron Homeostasis and Redox Balance in Cancer Cells

Zhang

Jin

et al. 2021

Front. Cell Dev. Biol.

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Iron is an essential trace mineral element in almost all living cells and organisms. However, cellular iron metabolism pathways are disturbed in most cancer cell types. Cancer cells have a high demand of iron. To maintain rapid growth and proliferation, cancer cells absorb large amounts of iron by altering expression of iron metabolism related proteins. However, iron can catalyze the production of reactive oxygen species (ROS) through Fenton reaction. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an important player in the resistance to oxidative damage by inducing the transcription of antioxidant genes. Aberrant activation of Nrf2 is observed in most cancer cell types. It has been revealed that the over-activation of Nrf2 promotes cell proliferation, suppresses cell apoptosis, enhances the self-renewal capability of cancer stem cells, and even increases the chemoresistance and radioresistance of cancer cells. Recently, several genes involving cellular iron homeostasis are identified under the control of Nrf2. Since cancer cells require amounts of iron and Nrf2 plays pivotal roles in oxidative defense and iron metabolism, it is highly probable that Nrf2 is a potential modulator orchestrating iron homeostasis and redox balance in cancer cells. In this hypothesis, we summarize the recent findings of the role of iron and Nrf2 in cancer cells and demonstrate how Nrf2 balances the oxidative stress induced by iron through regulating antioxidant enzymes and iron metabolism. This hypothesis provides new insights into the role of Nrf2 in cancer progression. Since ferroptosis is dependent on lipid peroxide and iron accumulation, Nrf2 inhibition may dramatically increase sensitivity to ferroptosis. The combination of Nrf2 inhibitors with ferroptosis inducers may exert greater efficacy on cancer therapy.

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“…DFP and DFX are oral iron chelators. All these iron chelators are shown to be effective in chelating iron from the heart and liver [91]. Several in vitro and in vivo studies demonstrated how iron overload alters bone balance.…”

Section: Iron Metabolism and Osteoporosismentioning

confidence: 99%

Iron Metabolism: From Inflammation to Cancer

A¹,

Tortora²,

Argenziano³

et al. 2021

annhematoloncol

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Iron is a trace element essential for several physiological cell functions and any alteration in its metabolism could be associated to the onset of several disorders. Cells normally avoid any dysregulation, activating fine molecular mechanisms to balance iron uptake, utilization, recycling, storage and export. The main “actors” in this event are hepcidin, ferroportin, ferritin and transferrin, both at cell and systemic level. Dysregulation in iron homeostasis is closely related to inflammation onset and perpetuation, osteoporosis and cancer progression. During inflammation, it has been observed a reduction in circulating iron as direct consequence of increase in ferritin levels, aimed to contain inflammatory processes and in many cases to restore the immune response. Iron overload directly promotes bone resorption and inhibits bone formation inducing osteoporosis. Moreover, iron cellular accumulation is responsible for ROS production with consequent DNA damage and neoplastic transformation of cells. In conclusion, even though many molecular mechanisms have to be clarified, targeting iron and also the mediators of its metabolism could be useful to manage a great variety of disorders, such inflammation, immune diseases, osteoporosis and cancer.

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Therapeutic potential of iron chelators on osteoporosis and their cellular mechanisms

Cited by 31 publications

References 118 publications

Iron overload‐induced ferroptosis of osteoblasts inhibits osteogenesis and promotes osteoporosis: An in vitro and in vivo study

Iron overload‐induced ferroptosis of osteoblasts inhibits osteogenesis and promotes osteoporosis: An in vitro and in vivo study

Nrf2 Is a Potential Modulator for Orchestrating Iron Homeostasis and Redox Balance in Cancer Cells

Iron Metabolism: From Inflammation to Cancer

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