Iron overload causes osteoporosis in thalassemia major patients through interaction with transient receptor potential vanilloid type 1 (TRPV1) channels

Rossi, Francesca; Perrotta, Silverio; Bellini, Giulia; Luongo, Livio; Tortora, Chiara; Siniscalco, Dario; Francese, Matteo; Torella, Annalaura; Nobili, Brúno; Marzo, Vincenzo Di; Maione, Sabatino

doi:10.3324/haematol.2014.104463

Cited by 70 publications

(74 citation statements)

References 49 publications

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“…Our understanding of thalassemia bone disease is incomplete given the complex piecemeal collection of risk factors which include hormonal deficiency, marrow expansion, iron toxicity, chelator toxicity and increased bone turnover (37)(38)(39)(40). These risk factors also impact on pubertal growth, nutrition and exercise and can lead to important changes in body composition and the inter-relationship between bone, fat and muscle (41).…”

Section: Epidemiology Of Thalassemia Bone Diseasementioning

confidence: 99%

Bone Disease in Thalassemia: A Molecular and Clinical Overview

et al. 2016

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Thalassemia bone disease is a common and severe complication of thalassemia-an inherited blood disorder due to mutations in the α or β hemoglobin gene. In its more severe form, severe anemia is present, and treatment with frequent red blood cell transfusion is necessary. Because the body has limited capacity to excrete iron, concomitant iron chelation is required to prevent the complications of iron overload. The effects of chronic anemia and iron overload can lead to multiple end-organ complications such as cardiomyopathy, increased risks of blood-borne diseases, and liver, pituitary, and bone disease. However, our understanding of thalassemia bone disease is incomplete and is composed of a complex piecemeal of risk factors that include genetic factors, hormonal deficiency, marrow expansion, skeletal dysmorphism, iron toxicity, chelators, and increased bone turnover. The high prevalence of bone disease in transfusion-dependent thalassemia is seen in both younger and older patients as life expectancy continues to improve. Indeed, hypogonadism and GH deficiency contribute to a failure to achieve peak bone mass in this group. The contribution of kidney dysfunction to bone disease in thalassemia is a new and significant complication. This coincides with studies confirming an increase in kidney stones and associated accelerated bone loss in the thalassemia cohort. However, multiple factors are also associated with reduced bone mineral density and include marrow expansion, iron toxicity, iron chelators, increased bone turnover, GH deficiency, and hypogonadism. Thalassemia bone disease is a composite of not only multiple hormonal deficiencies but also multiorgan diseases. This review will address the molecular mechanisms and clinical risk factors associated with thalassemia bone disease and the clinical implications for monitoring and treating this disorder.

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Section: Epidemiology Of Thalassemia Bone Diseasementioning

confidence: 99%

Bone Disease in Thalassemia: A Molecular and Clinical Overview

et al. 2016

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“…Although a TRPV1 agonist does not affect two biomarkers of femoral and lumbar bone mineral density in osteoclasts from thalassemic patients in vitro, it dramatically reduces osteoclast number (749). As genetic ablation or pharmacological inhibition of TRPV1 is beneficial for the restoration of quiescent osteoclast activity in ovariectomized mice, TRPV1 activation by endocannabinoids/ endovanilloids might be one of the cause of osteoporosis in these patients (747).…”

Section: Bonementioning

confidence: 99%

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

Ligresti¹,

Petrocellis²,

Marzo³

2016

Physiological Reviews

377

337

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Apart from having been used and misused for at least four millennia for, among others, recreational and medicinal purposes, the cannabis plant and its most peculiar chemical components, the plant cannabinoids (phytocannabinoids), have the merit to have led humanity to discover one of the most intriguing and pleiotropic endogenous signaling systems, the endocannabinoid system (ECS). This review article aims to describe and critically discuss, in the most comprehensive possible manner, the multifaceted aspects of 1) the pharmacology and potential impact on mammalian physiology of all major phytocannabinoids, and not only of the most famous one ⌬ 9 -tetrahydrocannabinol, and 2) the adaptive prohomeostatic physiological, or maladaptive pathological, roles of the ECS in mammalian cells, tissues, and organs. In doing so, we have respected the chronological order of the milestones of the millennial route from medicinal/recreational cannabis to the ECS and beyond, as it is now clear that some of the early steps in this long path, which were originally neglected, are becoming important again. The emerging picture is rather complex, but still supports the belief that more important discoveries on human physiology, and new therapies, might come in the future from new knowledge in this field.

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“…IO is associated with hereditary hemochromatosis or repeated blood transfusions for diseases such as beta thalassemia, bone marrow failure, or myelodysplastic syndrome [10][11][12][13][14]. Recently, iron accumulation has been shown to impair the bone marrow microenvironment and suppress the proliferation and differentiation of BMSCs, thus leading to lower bone mineral density and postmenopausal osteoporosis [15,16]. Oxidant stress has also been seen to be involved in iron overload-induced bone loss in mice [17].…”

Section: Introductionmentioning

confidence: 99%

Astragalus Polysaccharide Attenuated Iron Overload-Induced Dysfunction of Mesenchymal Stem Cells via Suppressing Mitochondrial ROS

Yang

Yan

et al. 2016

Cell Physiol Biochem

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Background/Aims: Bone marrow-derived mesenchymal stem cells (BMSCs) have the ability to differentiate into multilineage cells such as osteoblasts, chondrocytes, and cardiomyocytes. Dysfunction of BMSCs in response to pathological stimuli participates in the development of diseases such as osteoporosis. Astragalus polysaccharide (APS) is a major active ingredient of Astragalus membranaceus, a commonly used anti-aging herb in traditional Chinese medicine. The aim of this study was to investigate whether APS protects against iron overload-induced dysfunction of BMSCs and its underlying mechanisms. Methods: BMSCs were exposed to ferric ammonium citrate (FAC) with or without different concentrations of APS. The viability and proliferation of BMSCs were assessed by CCK-8 assay and EdU staining. Cell apoptosis, senescence and pluripotency were examined utilizing TUNEL staining, β-galactosidase staining and qRT-PCR respectively. The reactive oxygen species (ROS) level was assessed in BMSCs with a DCFH-DA probe and MitoSOX Red staining. Results: Firstly, we found that iron overload induced by FAC markedly reduced the viability and proliferation of BMSCs, but treatment with APS at 10, 30 and 100 μg/mL was able to counter the reduction of cell proliferation. Furthermore, exposure to FAC led to apoptosis and senescence in BMSCs, which were partially attenuated by APS. The pluripotent genes Nanog, Sox2 and Oct4 were shown to be downregulated in BMSCs after FAC treatment, however APS inhibited the reduction of Nanog, Sox2 and Oct4 expression. Further study uncovered that APS treatment abrogated the increase of intracellular and mitochondrial ROS level in FAC-treated BMSCs. Conclusion: Treatment of BMSCs with APS to impede mitochondrial ROS accumulation can remarkably inhibit apoptosis, senescence, and the reduction of proliferation and pluripotency of BMSCs caused by FAC-induced iron overload.

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Iron overload causes osteoporosis in thalassemia major patients through interaction with transient receptor potential vanilloid type 1 (TRPV1) channels

Abstract: ABSTRACTmineral density of the lumbar spine or the femoral neck.18

Cited by 70 publications

References 49 publications

Bone Disease in Thalassemia: A Molecular and Clinical Overview

Bone Disease in Thalassemia: A Molecular and Clinical Overview

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

Astragalus Polysaccharide Attenuated Iron Overload-Induced Dysfunction of Mesenchymal Stem Cells via Suppressing Mitochondrial ROS

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