Ferric ion could facilitate osteoclast differentiation and bone resorption through the production of reactive oxygen species

The Second Affiliated Hospital of Soochow University, Department of Orthopaedics, China, Jiangsu Province, 1055 Sanxiang Road, Suzhou, Jiangsu, China.
Journal of Orthopaedic Research (Impact Factor: 2.99). 11/2012; 30(11):1843-52. DOI: 10.1002/jor.22133
Source: PubMed


Iron overload is widely regarded as a risk factor for osteoporosis. It has been demonstrated that iron can inhibit osteoblast differentiation. However, the effects of iron on osteoclast differentiation and bone resorption remain controversial. In this study, we found that ferric ion promoted Receptor Activator of Nuclear Factor κ B Ligand (RANKL)-induced osteoclast (OC) formation in both RAW264.7 cells and bone marrow-derived macrophages (BMMs), and this effect was accompanied by elevated levels of reactive oxygen species (ROS) and oxidative stress. Moreover, this effect was attenuated by the administration of antioxidant N-acetyl-L-cysteine (NAC). Therefore, we conclude that ferric ion can promote osteoclast differentiation and bone resorption through the production of ROS. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1843-1852, 2012.

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    • "A global threshold was defined as the lowest mineral density. Calculation methods of bone parameters have been previously described [20]. The volumetric parameters of bone volume fraction (BVF), trabecular thickness (μm), trabecular number (no./mm), trabecular spacing (μm) and the thickness and area of cortices were assessed to investigate the effect of NAC and RES on the microarchitecture of the cortical bone at mid-diaphysis femur and trabecular bone from distal femur. "
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    ABSTRACT: Estrogen deficiency has been considered to be a major cause of osteoporosis, but recent epidemiological evidence and mechanistic studies have indicated that aging and the associated increase in reactive oxygen species (ROS) are the proximal pathogenic factors. Through ROS-mediated reactions, iron can induce disequilibrium of oxidation and antioxidation and can cause bone loss in mice. Therefore, we investigated the effects of resveratrol (RES) on bone mineral density, bone microstructure and the osteoblast functions under iron-overload conditions. Excess iron disrupted the antioxidant/prooxidant equilibrium of the mice and induced the defect and the lesion of the bone trabecula as well as disequilibrium between bone formation and bone resorption in iron-overload mice. Oral administration of RES significantly prevented bone loss in the osteoporotic mice. RES reversed the reduction of Runx2, OCN and type I collagen from excess iron; up-regulated the level of FOXO1; and maintained the antioxidant/prooxidant equilibrium in the mice. RES also reduced the ratio of OPG/RANKL in MC3T3-E1 cells and in mice and significantly inhibited subsequent osteoclastogenesis. These results provide new insights into the antiosteoporosis mechanisms of RES through antioxidative effects, suggesting that RES can be considered a potential natural resource for developing medicines or dietary supplements to prevent and treat osteoporosis. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jun 2015 · The Journal of nutritional biochemistry
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    • "Iron is a trace element that has important functions in vivo[63]. In the skeletal system, both excess and insufficient iron can reduce bone mass[64]–[66]. In vitro, iron can even inhibit the growth of hydroxyapatite crystals[67]. "
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    ABSTRACT: A hypomagnetic field is an extremely weak magnetic field-it is considerably weaker than the geomagnetic field. In deep-space exploration missions, such as those involving extended stays on the moon and interplanetary travel, astronauts will experience abnormal space environments involving hypomagnetic fields and microgravity. It is known that microgravity in space causes bone loss, which results in decreased bone mineral density. However, it is unclear whether hypomagnetic fields affect the skeletal system. In the present study, we aimed to investigate the complex effects of a hypomagnetic field and microgravity on bone loss. To study the effects of hypomagnetic fields on the femoral characteristics of rats in simulated weightlessness, we established a rat model of hindlimb unloading that was exposed to a hypomagnetic field. We used a geomagnetic field-shielding chamber to generate a hypomagnetic field of <300 nT. The results show that hypomagnetic fields can exacerbate bone mineral density loss and alter femoral biomechanical characteristics in hindlimb-unloaded rats. The underlying mechanism might involve changes in biological rhythms and the concentrations of trace elements due to the hypomagnetic field, which would result in the generation of oxidative stress responses in the rat. Excessive levels of reactive oxygen species would stimulate osteoblasts to secrete receptor activator of nuclear factor-κB ligand and promote the maturation and activation of osteoclasts and thus eventually cause bone resorption.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "In other words, excess iron promoted the activity of osteoclasts, and then elevated bone resorption process, with resultant loss of bone strength. In terms of the molecular mechanisms, previous studies have demonstrated that intracellular iron retention would cause massive production of reactive oxygen species (ROS) through Fenton reaction (Fridovich, 1978; Galaris and Pantopoulos, 2008; Halliwell and Gutteridge, 1990), and ROS is postulated to be an instigator of bone resorption (Jia et al., 2012). Jia and colleagues demonstrated that iron overload could promote osteoclast differentiation and bone resorption through stimulation of ROS (Ishii et al., 2009; Yamasaki and Hagiwara, 2009). "
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    ABSTRACT: Osteoporosis is one of leading disorders among aged people. Bone loss results from a number of physiological alterations, such as estrogen decline and aging. Meanwhile, iron overload has been recognized as a risk factor for bone loss. Systemic iron homeostasis is fundamentally governed by the hepcidin-ferroportin regulatory axis, where hepcidin is the key regulator. Hepcidin deficiency could induce a few disorders, of which iron overload is the most representative phenotype. However, there was little investigation of the effects of hepcidin deficiency on bone metabolism. To this end, hepcidin-deficient (Hamp1(-/-)) mice were employed to address this issue. Our results revealed that significant iron overload was induced in Hamp1(-/-) mice. Importantly, significant decreases of maximal loading and maximal bending stress were found in Hamp1(-/-) mice relative to wildtype (WT) mice. Moreover, the levels of the C-telopeptide of type I collagen (CTX-1) increased in Hamp1(-/-) mice. Therefore, hepcidin deficiency resulted in a marked reduction of bone load-bearing capacity likely through enhancing bone resorption, suggesting a direct correlation between hepcidin deficiency and bone loss. Targeting hepcidin or the pathway it modulates may thus represent a therapeutic for osteopenia or osteoporosis.
    Full-text · Article · Feb 2014 · Gene
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