Abstract
One of the potential contributing factors for iron overload-induced osteoporosis is the iron toxicity on bone forming cells, osteoblasts. In this study, the comparative effects of Fe3+ and Fe2+ on osteoblast differentiation and mineralization were studied in UMR-106 osteoblast cells by using ferric ammonium citrate and ferrous ammonium sulfate as Fe3+ and Fe2+ donors, respectively. Effects of 1,25 dihydroxyvitamin D3 [1,25(OH)2D3] and iron chelator deferiprone on iron uptake ability of osteoblasts were examined, and the potential protective ability of 1,25(OH)2D3, deferiprone and extracellular calcium treatment in osteoblast cell survival under iron overload was also elucidated. The differential effects of Fe3+ and Fe2+ on reactive oxygen species (ROS) production in osteoblasts were also compared. Our results showed that both iron species suppressed alkaline phosphatase gene expression and mineralization with the stronger effects from Fe3+ than Fe2+. 1,25(OH)2D3 significantly increased the intracellular iron but minimally affected osteoblast cell survival under iron overload. Deferiprone markedly decreased intracellular iron in osteoblasts, but it could not recover iron-induced osteoblast cell death. Interestingly, extracellular calcium was able to rescue osteoblasts from iron-induced osteoblast cell death. Additionally, both iron species could induce ROS production and G0/G1 cell cycle arrest in osteoblasts with the stronger effects from Fe3+. In conclusions, Fe3+ and Fe2+ differentially compromised the osteoblast functions and viability, which can be alleviated by an increase in extracellular ionized calcium, but not 1,25(OH)2D3 or iron chelator deferiprone. This study has provided the invaluable information for therapeutic design targeting specific iron specie(s) in iron overload-induced osteoporosis. Moreover, an increase in extracellular calcium could be beneficial for this group of patients.
Highlights
Iron overload could be a result from an increase in iron absorption, ineffective erythropoiesis and regular blood transfusion [1,2]
Osteoblast differentiation was determined by the expression of osteoblast differentiation factors, and iron overload has been reported to contribute to osteoblast differentiation impairment [9,45,46]
This study aimed to investigate the effects of two iron species, ferric (Fe3 +) and ferrous (Fe2+), on the expression of osteoblast differentiation factors including runtrelated transcription factor 2 (Runx2), alkaline phosphatase (ALP), collagen type 1A and osteocalcin by Quantitative real-time PCR (qRT-PCR)
Summary
Iron overload could be a result from an increase in iron absorption, ineffective erythropoiesis and regular blood transfusion [1,2]. These conditions are commonly found in several diseases, e.g., β-thalassemia, hereditary hemochromatosis and sickle cell anemia [3,4,5]. Free-ionized non-heme Fe3+ iron must be reduced to Fe2+ by ferric reductase duodenal cytochrome b (DcytB) before being transported into cells, mostly via divalent metal transporter (DMT)-1. Excess free iron in the cells could participate in redox reaction for reactive oxygen species (ROS) production through interconverting between Fe3+ and Fe2+, leading to organ damage and a number of diseases, e.g., fibrosis, liver injury, heart failure, diabetes mellitus, neurodegenerative diseases and bone loss [5,16,17]
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