Wnt5a is a key target for the pro-osteogenic effects of iron chelation on osteoblast progenitors

Baschant, Ulrike; Rauner, Martina; Balaian, Ekaterina; Weidner, Heike; Roetto, Antonella; Platzbecker, Uwe; Hofbauer, Lorenz C.

doi:10.3324/haematol.2016.144808

Cited by 52 publications

(38 citation statements)

References 53 publications

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“…The use of an iron chelator will be an ideal therapy for significantly increasing bone mineral density (BMD) in patients with hematonosis, whose serum ferritin levels reach iron overload (>1000 ng/mL) (Poggi et al 2016). Moreover, osteoblast are inhibited by high iron levels, and this inhibition is reversed upon treatment with iron chelators or hepcidin , Baschant et al 2016. However, ferritin levels, which are 2-3 times higher than normal values of 12-150 ng/mL in postmenopausal patients with osteoporosis, do not reach iron overload but rather reflect iron accumulation (Fucharoen & Paiboonsukwongi 2015).…”

Section: Discussionmentioning

confidence: 99%

Hepcidin is an endogenous protective factor for osteoporosis by reducing iron levels

Zhang

Wang

et al. 2018

Journal of Molecular Endocrinology

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Postmenopausal osteoporosis is a global health issue. Although a lack of estrogen is considered the major reason for postmenopausal osteoporosis, other factors might also contribute the etiology of the disease. In previous reports, we and others proposed that iron accumulation after menopause accelerates osteoporosis, and here, we genetically modified the expression of an endogenous hormone, hepcidin, to modulate iron status in a mouse model. Our results show that hepcidin levels negatively correlate with bone loss in both knockout and overexpression (with ovariectomy) murine models. In addition, iron overload enhances reactive oxygen species (ROS) activity and attenuates the functions of primary osteoblasts, while iron depletion could reverse this phenomenon through inhibiting the functions of primary osteoclasts. Therefore, our results provide more evidence of the 'iron accumulation' hypothesis, which suggests that high iron levels are risk factors for osteoporosis, and the 'Huang's hypothesis' that hepcidin is a potential drug target for the prevention of postmenopausal osteoporosis.

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Section: Discussionmentioning

confidence: 99%

Hepcidin is an endogenous protective factor for osteoporosis by reducing iron levels

Zhang

Wang

et al. 2018

Journal of Molecular Endocrinology

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“…Previous studies have suggested that iron metabolism is closely associated with bone physiology [25]. Baschant et al showed that attenuated osteogenic differentiation was observed in the presence of excess iron, whereas elevated osteogenic differentiation was observed in the presence of the iron chelator (DFO) [25].…”

Section: Discussionmentioning

confidence: 99%

Deferoxamine-Induced Migration and Odontoblast Differentiation via ROS-Dependent Autophagy in Dental Pulp Stem Cells

Wang

Jiang

et al. 2017

Cell Physiol Biochem

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Background/Aims: As a vital degradation and recycling system, autophagy plays an essential role in regulating the differentiation of stem cells. We previously showed that iron chelator deferoxamine (DFO) could promote the repair ability of dental pulp stem cells (DPSCs). Here, we investigated the effect of DFO in autophagy and the role of autophagy in regulating the migration and odontoblast differentiation of DPSCs. Methods: Transmission electron microscopy, immunofluorescence staining and western blotting were performed to evaluate the autophagic activity of DPSCs. Transmigration assay, alkaline phosphatase staining/activity, alizarin red S staining and quantitative PCR were performed to examine the migration and odontoblast differentiation of DPSCs. Reactive oxygen species (ROS) levels and the effects of ROS scavenger in autophagy induction were also detected. Autophagy inhibitors (3-MA and bafilomycin A1) and lentiviral vectors carrying ATG5 shRNA sequences were used for autophagy inhibition. Results: Early exposure to DFO promoted the mineralization of DPSCs and increased autophagic activity. Autophagy inhibition suppressed DFO-induced DPSC migration and odontoblast differentiation. Furthermore, DFO treatment could induce autophagy partly through hypoxia-inducible factor 1α/B cell lymphoma 2/adenovirus E1B 19K-interacting protein 3 (HIF-1α/BNIP3) pathway in a ROS-dependent manner. Conclusion: DFO increased DPSC migration and differentiation, which might be modulated through ROS-induced autophagy.

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“…Furthermore, both Wnt and TCF1 can synergistically enhance RUNX2 promoter activity during osteoblastogenesis [94]. In fact, Wnt 3a, Wnt 5a, and Wnt 16 drive pro-osteogenic effects [95,96], while Wnt 1 has an anti-osteogenic effect on osteoblast progenitor cells [97].…”

Section: The Interplay Between Sirt1 and The Wnt/β-catenin Pathway Inmentioning

confidence: 99%

Sirtuin-1 and Its Relevance in Vascular Calcification

Liao

Hou

et al. 2020

IJMS

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Vascular calcification (VC) is highly associated with cardiovascular disease and all-cause mortality in patients with chronic kidney disease. Dysregulation of endothelial cells and vascular smooth muscle cells (VSMCs) is related to VC. Sirtuin-1 (Sirt1) deacetylase encompasses a broad range of transcription factors that are linked to an extended lifespan. Sirt1 enhances endothelial NO synthase and upregulates FoxOs to activate its antioxidant properties and delay cell senescence. Sirt1 reverses osteogenic phenotypic transdifferentiation by influencing RUNX2 expression in VSMCs. Low Sirt1 hardly prevents acetylation by p300 and phosphorylation of β-catenin that, following the facilitation of β-catenin translocation, drives osteogenic phenotypic transdifferentiation. Hyperphosphatemia induces VC by osteogenic conversion, apoptosis, and senescence of VSMCs through the Pit-1 cotransporter, which can be retarded by the sirt1 activator resveratrol. Proinflammatory adipocytokines released from dysfunctional perivascular adipose tissue (PVAT) mediate medial calcification and arterial stiffness. Sirt1 ameliorates release of PVAT adipokines and increases adiponectin secretion, which interact with FoxO 1 against oxidative stress and inflammatory arterial insult. Conclusively, Sirt1 decelerates VC by means of influencing endothelial NO bioavailability, senescence of ECs and VSMCs, osteogenic phenotypic transdifferentiation, apoptosis of VSMCs, ECM deposition, and the inflammatory response of PVAT. Factors that aggravate VC include vitamin D deficiency-related macrophage recruitment and further inflammation responses. Supplementation with vitamin D to adequate levels is beneficial in improving PVAT macrophage infiltration and local inflammation, which further prevents VC.

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Wnt5a is a key target for the pro-osteogenic effects of iron chelation on osteoblast progenitors

Cited by 52 publications

References 53 publications

Hepcidin is an endogenous protective factor for osteoporosis by reducing iron levels

Hepcidin is an endogenous protective factor for osteoporosis by reducing iron levels

Deferoxamine-Induced Migration and Odontoblast Differentiation via ROS-Dependent Autophagy in Dental Pulp Stem Cells

Sirtuin-1 and Its Relevance in Vascular Calcification

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