Desferoxamine protects against glucocorticoid‐induced osteonecrosis of the femoral head via activating HIF‐1α expression

Jing, Xingzhi; Du, Tao; Yang, Xiaoxia; Zhang, Weimin; Wang, Guodong; Liu, Xiaoyang; Li, Tao; Jiang, Zhensong

doi:10.1002/jcp.29799

Cited by 38 publications

(32 citation statements)

References 36 publications

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“…The linkage of p62 to ubiquitin on the mitochondria and LC3-II (the lipidated form of LC3) on autophagosomes provides a physical attachment point for mitophagy (Geisler et al, 2010;Palikaras et al, 2018), and disruption of either PINK1 or Parkin leads to the impaired mitophagy (Han et al, 2015;Lazarou et al, 2015). Interestingly, impaired mitophagic function have been reported to negatively impact osteoblast differentiation and mineralization function in vitro (Shen et al, 2018b;Jing et al, 2020) and the restoration of mitophagy helps alleviate steriod-induced bone loss in vivo (Zhang et al, 2020). Despite these encouraging reports, the precise role of autophagy and mitophagy in osteoblastic differentiation and function has not been thoroughly explored.…”

Section: Introductionmentioning

confidence: 99%

Vitamin K2 Can Rescue the Dexamethasone-Induced Downregulation of Osteoblast Autophagy and Mitophagy Thereby Restoring Osteoblast Function In Vitro and In Vivo

et al. 2020

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Chronic long-term glucocorticoids (GC) use is associated with glucocorticoid-induced osteoporosis (GIOP) by inhibiting the survival and impairing the functions of osteoblasts. Autophagy and mitophagy play key roles in osteoblast differentiation, mineralization and survival, and mounting evidence have implicated osteoblast autophagy and mitophagy as a novel mechanism in the pathogenesis of GIOP. Vitamin K2 (VK2) is an essential nutrient supplement that have been shown to exert protective effects against osteoporotic bone loss including GIOP. In this study, we showed that the glucocorticoid dexamethasone (Dex) deregulated osteoblast autophagy and mitophagy by downregulating the expression of autophagic and mitophagic markers LC3-II, PINK1, Parkin. This consequently led to inhibition of osteoblast differentiation and mineralization function in vitro. Interestingly, co-treatment with VK2 significantly attenuated the Dex-induced downregulation of LC3-II, PINK1, Parkin, thereby restoring autophagic and mitophagic processes and normal osteoblastic activity. In addition, using an established rat model of GIOP, we showed that VK2 administration can protect rats against the deleterious effects of Dex on bone by reinstating autophagic and mitophagic activities in bone tissues. Collectively, our results provide new insights into the role of osteoblast autophagy and mitophagy in GIOP. Additionally, the use of VK2 supplementation to augment osteoblast autophagy/mitophagy may significantly improve clinical outcomes of GIOP patients.

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Section: Introductionmentioning

confidence: 99%

Vitamin K2 Can Rescue the Dexamethasone-Induced Downregulation of Osteoblast Autophagy and Mitophagy Thereby Restoring Osteoblast Function In Vitro and In Vivo

et al. 2020

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“…Long-term use of excessive GCs not only activate OC but also decrease osteogenic differentiation and angiogenesis, all of which lead to the osteonecrosis [ 1 , 4 , 21 , 23 ]. As the literature shows, GCs exert effects in downregulating of the wnt/ β -catenin signal pathway, which inhibits the osteogenic differentiation but increases the adipogenic differentiation, resulting in the occurrence of GIOFH [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…As the literature shows, GCs exert effects in downregulating of the wnt/ β -catenin signal pathway, which inhibits the osteogenic differentiation but increases the adipogenic differentiation, resulting in the occurrence of GIOFH [ 30 ]. In addition, HIF-1 α is a key factor response to ischemia hypoxia and increased in the early GIOFH; hence, the HIF-1 α /VEGF pathway was upregulated and moreover the downstream factor VEGF was also increased [ 21 , 31 ]. However, with the continuous effects of GCs, HIF-1 α /VEGF regulated by the PI3K/AKT pathway was inhibited and the angiogenesis was decreased especially in late ONFH [ 23 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

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Combined Pharmacotherapy with Alendronate and Desferoxamine Regulate the Bone Resorption and Bone Regeneration for Preventing Glucocorticoids-Induced Osteonecrosis of the Femoral Head

Sheng

Lao

Zhang

et al. 2020

BioMed Research International

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Background. Osteonecrosis of the femoral head (ONFH) is a challenge for surgeons and is still without effective treatment method. This study is aimed at evaluating the combined pharmacotherapy with alendronate and desferoxamine for preventing glucocorticoid-induced osteonecrosis of the femoral head (GIOFH) and evaluating the efficacy of the combined medicine in regulating the bone resorption and bone regeneration. Materials and Methods. Thirty-six rats were randomly assigned to three groups: group A received alendronate and desferoxamine (n=12), group B received alendronate only (n=12), and group C acted as the control group received placebo (n=12). All rats induced the GIOFH using methylprednisolone combined with lipopolysaccharide. Eight weeks later, all rats were killed and their tissues were subjected to radiographic and histological analyses. Results. According to the results, alendronate administration improved the trabecular thickness and separation in micro-CT analysis but had no significant evidence in increasing the bone area and decreasing the ratio of osteocyte lacunae in histological analysis when compared with the control group. Meanwhile, the alendronate group had more OCs, but less OCN and VEGF levels along with decreased p-AKT, HIF-1α, RANKL, and NFATc1 expressions than the control group. For comparison, alendronate combined with DFO further improved the bone volume, trabecular number, trabecular separation, and trabecular thickness with lower ratio of osteocyte lacunae and OC number, higher expression of OCN and VEGF and upregulated signal factors of HIF-1α and β-catenin, and decreased RANKL and NFATc1. Conclusion. Combined pharmacotherapy with alendronate and desferoxamine provide significant effects in regulating the bone resorption and bone regeneration for preventing GIOFN.

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“…VEGF is a key regulator of angiogenesis, VEGF overexpressed adipose stem cells can provide rapid angiogenesis and osteogenesis in inhospitable avascular environments of ONFH [36]. Desferrioxamine ameliorates glucocorticoid-induced ONFH by inducing angiogenesis via HIF-1α/VEGF pathway [37]. Exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells mediate a protective effect in ONFH by inducing local angiogenesis via the activation of the PI3K/Akt signaling pathway [38].…”

Section: Discussionmentioning

confidence: 99%

MiR-150-5p-modified Bone Marrow Mesenchymal Stem Cells Derived Exosomes Ameliorate Osteonecrosis of Femoral Head by Promoting Endothelial Cell Angiogenesis

Fang¹,

He²,

Jiang³

et al. 2020

Preprint

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Background: Osteonecrosis of femoral head (ONFH) is a common ischemic disease that induces femoral head necrosis. The role of exosomes and miRNA in ONFH has been elucidated, however, whether miRNA-modified exosomes improve the therapy of ONFH is not clear.Methods: We screened ONFH-related miRNAs by RNA sequencing in plasma exosomes of ONFH patients and healthy donors. The key miRNA was overexpressed in bone marrow mesenchymal stem cells (BMSC) exosomes. The regulatory functions of miRNA-modified BMSC exosomes in vascular endothelial cells were illustrated through angiogenesis assay and scratch assay.Results: We identified 9 differently expressed miRNAs (DEmiRNAs) in plasma exosomes between ONFH and healthy groups, with 6 up-regulated and 3 down-regulated miRNAs. Function and pathway analysis revealed DEmiRNAs were primarily involved in angiogenesis, cell migration, focal adhesion. Moreover, miR-150-5p was declined in ONFH exosomes and regulated multiple angiogenesis-related pathways. The miR-150-5p-overexpressed BMSC exosomes were successfully obtained and transported miR-150-5p to endothelial cells. Moreover, the miR-150-5p-modified BMSC exosomes promoted the angiogenesis and migration of endothelial cells.Conclusion: Our results elucidate the exosomal miRNA expression profiles in ONFH, and miR-150-5p-modified BMSC exosomes protect against ONFH by promoting angiogenesis, suggesting a new molecular knowledge for the clinical application of ONFH.

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Desferoxamine protects against glucocorticoid‐induced osteonecrosis of the femoral head via activating HIF‐1α expression

Cited by 38 publications

References 36 publications

Vitamin K2 Can Rescue the Dexamethasone-Induced Downregulation of Osteoblast Autophagy and Mitophagy Thereby Restoring Osteoblast Function In Vitro and In Vivo

Vitamin K2 Can Rescue the Dexamethasone-Induced Downregulation of Osteoblast Autophagy and Mitophagy Thereby Restoring Osteoblast Function In Vitro and In Vivo

Combined Pharmacotherapy with Alendronate and Desferoxamine Regulate the Bone Resorption and Bone Regeneration for Preventing Glucocorticoids-Induced Osteonecrosis of the Femoral Head

MiR-150-5p-modified Bone Marrow Mesenchymal Stem Cells Derived Exosomes Ameliorate Osteonecrosis of Femoral Head by Promoting Endothelial Cell Angiogenesis

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