Abstract
Recently, more and more studies indicate that iron overload would cause osteopenia or osteoporosis. However, the molecular mechanism of it remains unclear. Moreover, very little is known about the iron metabolism in bone tissue at present. Therefore, the mRNA expression of iron-regulators, transferrin receptor1 (Tfr1), divalent metal transporter1 (Dmt1 + IRE and Dmt1 − IRE), ferritin (FtH and FtL), and ferroportin1 (Ireg1), and the localization of ferroportin1 protein were examined in the bone tissue of rats. In addition, the mRNA expression of each gene was compared between groups of rats with and without iron overload. The results showed that ferroportin1 protein was localized in the cytoplasm of osteoblast, osteocyte, chondrocyte and osteoclast of rats’ femur. The six iron-regulatory genes, Tfr1, ferritin (FtH and FtL), (Dmt1 + IRE and Dmt1 − IRE) and ferroportin1 (Ireg1), were found in femurs of rats. In addition, significantly up-regulated expression of FtH and FtL mRNA, and markedly down-regulated expression of Tfr1, Dmt1 + IRE and Ireg1 mRNA, were observed in the iron overload group compared with the control group. The result indicates that ferroportin1 protein is localized in the cytoplasm of bone cells of rats. Tfr1, Dmt1, ferritin and ferroportin1 exist in bone tissue of rats, and they may be involved in the pathological process of iron overload-induced bone lesion.
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Chen YM, Qian ZM, Du JR, Duan XL, Chang YZ, Wang Q, Wang CY, Ma YM, Xu YJ, Li LZ, Ke Y (2005) Iron loading inhibits ferroportin1 expression in PC12 cells. Neurochem Int 47:507–513
Cheng QA, Zhang XF, Jiang J, Zhao GY, Wang Y, Xu YJ, Xu XM, Ma HL (2017) postmenopausal iron overload exacerbated bone loss by promoting the degradation of type I collagen. Biomed Res Int. https://doi.org/10.1155/2017/1345193
Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt SJ, Moynihan J, Paw BH, Drejer A, Barut B, Zapata A, Law TC, Brugnara C, Lux SE, Pinkus GS, Pinkus JL, Kingsley PD, Palis J, Fleming MD, Andrews NC, Zon LI (2000) Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403:776–781
Donovan A, Lima C, Andrews NC (2003) Analysis of iron homeostasis in mice with a targeted deletion of the gene encoding the iron exporter Ferroportin 1 (Fpn1). Blood 102:157a
Doyard M, Chappard D, Leroyer P, Roth MP, Loreal O, Guggenbuhl P (2016) Decreased bone formation explains osteoporosis in a genetic mouse model of hemochromatosiss. PLoS ONE 11:e0148292
Frazer DM, Wilkins SJ, Becker EM, Murphy TL, Vulpe CD, McKie AT, Anderson GJ (2003) A rapid decrease in the expression of DMT1 and Dcytb but not Ireg1 or hephaestin explains the mucosal block phenomenon of iron absorption. Gut 52:340–346
Galli A, Bergamaschi G, Recalde H, Biasiotto G, Santambrogio P, Boggi S, Levi S, Arosio P, Cazzola M (2004) Ferroportin gene silencing induces iron retention and enhances ferritin synthesis in human macrophages. Br J Haematol 127:598–603
Ganz T (2005) Cellular iron: ferroportin is the only way out. Cell Metab 1:155–157
Gruenheid S, Canonne-Hergaux F, Gauthier S, Hackam DJ, Grinstein S, Gros P (1999) The iron transport protein NRAMP2 is an integral membrane glycoprotein that colocalizes with transferrin in recycling endosomes. J Exp Med 189:831–841
He YF, Ma Y, Gao C, Zhao GY, Zhang LL, Li GF, Pan YZ, Li K, Xu YJ (2013) Iron overload inhibits osteoblast biological activity through oxidative stress. Biol Trace Elem Res 152:292–296
Hubert N, Hentze MW (2002) Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function. PNA Sci 99:12345–12350
Jeney V (2017) Clinical impact and cellular mechanisms of iron overload-associated bone loss. Front Pharmacol 8:77
Kasai K, Hori MT, Goodman WG (1990) Characterization of the transferrin receptor in UMR-106-01 osteoblast-like cells. Endocrinology 126:1742–1749
Ke JY, Cen WJ, Zhou XZ, Li YR, Kong WD, Jiang JW (2017) Iron overload induces apoptosis of murine preosteoblast cells via ROS and inhibition of AKT pathway. Oral Dis 23:784–794
Klausner RD, Rouault TA, Harford JB (1993) Regulating the fate of mRNA: the control of cellular iron metabolism. Cell 72:19–28
Leong WI, Lonnerdal B (2005) Iron transporters in rat mammary gland: effects of different stages of lactation and maternal iron status. Am J Clin Nutr 81:445–453
Leong WI, Bowlus CL, Tallkvist J, Lonnerdal B (2003) DMT1 and FPN1 expression during infancy: developmental regulation of iron absorption. Am J Physiol Gastr 285:G1153–G1161
Li YQ, Bai B, Zheng QQ, Yan H, Zhuang GH (2013) Quantitative study of iron metabolism-related genes expression in rat. Biomed Environ Sci 26:808–819
Messer JG, Kilbarger AK, Erikson KM, Kipp DE (2009) Iron overload alters iron-regulatory genes and proteins, down-regulates osteoblastic phenotype, and is associated with apoptosis in fetal rat calvaria cultures. Bone 45:972–979
Messer JG, Cooney PT, Kipp DE (2010) Iron chelator deferoxamine alters iron-regulatory genes and proteins and suppresses osteoblast phenotype in fetal rat calvaria cells. Bone 46:1408–1415
Mims MP, Prchal JT (2005) Divalent metal transporter 1. Hematology 10:339–345
Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306:2090–2093
Rice AE, Mendez MJ, Hokanson CA, Rees DC, Bjorkman PJ (2009) Investigation of the biophysical and cell biological properties of ferroportin, a multipass integral membrane protein iron exporter. J Mol Biol 386:717–732
Saki N, Abroun S, Salari F, Rahim F, Shahjahani M, Javad MA (2015) Molecular aspects of bone resorption in beta-Thalassemia major. Cell J 17:193–200
Spanner M, Weber K, Lanske B, Ihbe A, Siggelkow H, Schutze H, Atkinson MJ (1995) The iron-binding protein ferritin is expressed in cells of the osteoblastic lineage in vitro and in vivo. Bone 17:161–165
Tabuchi M, Yoshimori T, Yamaguchi K, Yoshida T, Kishi F (2000) Human NRAMP2/DMT1, which mediates iron transport across endosomal membranes, is localized to late endosomes and lysosomes in HEp-2 cells. J Biol Chem 275:22220–22228
Tian Q, Wu S, Dai Z, Yang J, Zheng J, Zheng Q, Liu Y (2016) Iron overload induced death of osteoblasts in vitro: involvement of the mitochondrial apoptotic pathway. Peer J 4:e2611
Tsay J, Yang Z, Ross FP, Cunningham-Rundles S, Lin H, Coleman R, Mayer-Kuckuk P, Doty SB, Grady RW, Giardina PJ, Boskey AL, Vogiatzi MG (2010) Bone loss caused by iron overload in a murine model: importance of oxidative stress. Blood 116:2582–2589
Tzoulis P, Ang AL, Shah FT, Berovic M, Prescott E, Jones R, Barnard M (2014) Prevalence of low bone mass and vitamin D deficiency in beta-thalassemia major. Hemoglobin 38:173–178
Valizadeh N, Farrokhi F, Alinejad V, Said Mardani S, Valizadeh N, Hejazi S, Noroozi M (2014) Bone density in transfusion dependent thalassemia patients in Urmia, Iran. Iran J Ped Hematol Oncol 4:68–71
Weinberg ED (2006) Iron loading: a risk factor for osteoporosis. Biometals 19:633–635
Xiao W, Beibei F, Guangsi S, Yu J, Wen Z, Xi H, Youjia X (2015) Iron overload increases osteoclastogenesis and aggravates the effects of ovariectomy on bone mass. J Endocrinol 226:121–134
Xie W, Lorenz S, Dolder S, Hofstetter W (2016) Extracellular iron is a modulator of the differentiation of osteoclast lineage cells. Calcif Tissue Int 98:275–283
Yang FM, Haile DJ, Wang XC, Dailey LA, Stonehuerner JG, Ghio AJ (2005) Apical location of ferroportin 1 in airway epithelia and its role in iron detoxification in the lung. Am J Physiol Lung C 289:L14–L23
Zarjou A, Jeney V, Arosio P, Poli M, Zavaczki E, Balla G, Balla J (2010) Ferritin ferroxidase activity: a potent inhibitor of osteogenesis. J Bone Miner Res 25:164–172
Zhang WL, Meng HZ, Yang MW (2015) Regulation of DMT1 on bone microstructure in type 2 diabetes. Int J Med Sci 12:441–449
Zhao L, Wang Y, Wang Z, Xu Z, Zhang Q, Yin M (2015) Effects of dietary resveratrol on excess-iron-induced bone loss via antioxidative character. J Nutr Biochem 26:1174–1182
Funding
This study was funded by the Fundamental Research Funds for the Central Universities (No. xjj2012137) and Shaanxi Province Government Research Grant (Nos. 2015JM8452; 2016SF-019).
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Li, Y., Bai, B. & Zhang, Y. Expression of iron-regulators in the bone tissue of rats with and without iron overload. Biometals 31, 749–757 (2018). https://doi.org/10.1007/s10534-018-0133-3
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DOI: https://doi.org/10.1007/s10534-018-0133-3