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Therapeutic Effect of Deferoxamine on Iron Overload-Induced Inhibition of Osteogenesis in a Zebrafish Model

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Abstract

Osteoporosis results from an imbalance in bone remodeling, in which osteoclastic bone resorption exceeds osteoblastic bone formation. Iron has recently been recognized as an independent risk factor for osteoporosis. Reportedly, excess iron could promote osteoclast differentiation and bone resorption through the production of reactive oxygen species (ROS). We evaluated the effect of iron on osteoblast differentiation and bone formation in zebrafish and further investigated the potential benefits of deferoxamine (DFO), a powerful iron chelator, in iron-overloaded zebrafish. The zebrafish model of iron overload described in this study demonstrated an apparent inhibition of bone formation, accompanied by decreased expression of osteoblast-specific genes (runx2a, runx2b, osteocalcin, osteopontin, ALP, and collagen type I). The negative effect of iron on osteoblastic activity and bone formation could be attributed to increased ROS generation and oxidative stress. Most importantly, we revealed that DFO was capable of removing whole-body iron and attenuating oxidative stress in iron-overloaded larval zebrafish, which facilitated larval recovery from the reductions in bone formation and osteogenesis induced by iron overload.

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References

  1. Kanis JA, Melton LJ 3rd, Christiansen C, Johnston CC, Khaltaev N (1994) The diagnosis of osteoporosis. J Bone Miner Res 9(8):1137–1141

    Article  CAS  PubMed  Google Scholar 

  2. Melton LJ 3rd, Johnell O, Lau E, Mautalen CA, Seeman E (2004) Osteoporosis and the global competition for health care resources. J Bone Miner Res 19(7):1055–1058

    Article  PubMed  Google Scholar 

  3. Mithal A, Kaur P (2012) Osteoporosis in Asia: a call to action. Curr Osteoporos Rep 10(4):245–247

    Article  PubMed  Google Scholar 

  4. Weinberg ED (2006) Iron loading: a risk factor for osteoporosis. Biometals 19(6):633–635

    Article  CAS  PubMed  Google Scholar 

  5. Guggenbuhl P, Deugnier Y, Boisdet JF, Rolland Y, Perdriger A, Pawlotsky Y, Chales G (2005) Bone mineral density in men with genetic hemochromatosis and HFE gene mutation. Osteoporos Int 16(12):1809–1814

    Article  CAS  PubMed  Google Scholar 

  6. Lorincz G, Traub NE, Chuke PO, Hussain SF (1974) African haemosiderosis associated with osteoporosis and vertebral collapse. East Afr Med J 51(6):488–495

    CAS  PubMed  Google Scholar 

  7. Salama OS, Al-Tonbary YA, Shahin RA, Eldeen OA (2006) Unbalanced bone turnover in children with beta-thalassemia. Hematology 11(3):197–202

    Article  CAS  PubMed  Google Scholar 

  8. Sarrai M, Duroseau H, D’Augustine J, Moktan S, Bellevue R (2007) Bone mass density in adults with sickle cell disease. Br J Haematol 136(4):666–672

    Article  CAS  PubMed  Google Scholar 

  9. Kim BJ, Ahn SH, Bae SJ, Kim EH, Lee SH, Kim HK, Choe JW, Koh JM, Kim GS (2012) Iron overload accelerates bone loss in healthy postmenopausal women and middle-aged men: a 3-year retrospective longitudinal study. J Bone Miner Res 27(11):2279–2290

    Article  CAS  PubMed  Google Scholar 

  10. Xu Y, Sirois P, Li K (2010) Iron overload plays a unique role in osteoporosis. Blood. http://bloodjournal.hematologylibrary.org/content/116/14/2582.full/reply#bloodjournal_el_524. Accessed 9 Sept 2010

  11. 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(14):2582–2589

    Article  CAS  PubMed  Google Scholar 

  12. Jia P, Xu YJ, Zhang ZL, Li K, Li B, Zhang W, Yang H (2012) Ferric ion could facilitate osteoclast differentiation and bone resorption through the production of reactive oxygen species. J Orthop Res 30(11):1843–1852

    Article  CAS  PubMed  Google Scholar 

  13. Yamasaki K, Hagiwara H (2009) Excess iron inhibits osteoblast metabolism. Toxicol Lett 191(2–3):211–215

    Article  CAS  PubMed  Google Scholar 

  14. Doyard M, Fatih N, Monnier A, Island ML, Aubry M, Leroyer P, Bouvet R, Chales G, Mosser J, Loreal O, Guggenbuhl P (2012) Iron excess limits HHIPL-2 gene expression and decreases osteoblastic activity in human MG-63 cells. Osteoporos Int 23(10):2435–2445

    Article  CAS  PubMed  Google Scholar 

  15. de Vernejoul MC, Pointillart A, Golenzer CC, Morieux C, Bielakoff J, Modrowski D, Miravet L (1984) Effects of iron overload on bone remodeling in pigs. Am J Pathol 116(3):377–384

    PubMed  Google Scholar 

  16. Barbazuk WB, Korf I, Kadavi C, Heyen J, Tate S, Wun E, Bedell JA, McPherson JD, Johnson SL (2000) The syntenic relationship of the zebrafish and human genomes. Genome Res 10(9):1351–1358

    Article  CAS  PubMed  Google Scholar 

  17. Barut BA, Zon LI (2000) Realizing the potential of zebrafish as a model for human disease. Physiol Genomics 2(2):49–51

    CAS  PubMed  Google Scholar 

  18. Fleming A, Sato M, Goldsmith P (2005) High-throughput in vivo screening for bone anabolic compounds with zebrafish. J Biomol Screen 10(8):823–831

    Article  CAS  PubMed  Google Scholar 

  19. Yu PB, Hong CC, Sachidanandan C, Babitt JL, Deng DY, Hoyng SA, Lin HY, Bloch KD, Peterson RT (2008) Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol 4(1):33–41

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Du SJ, Frenkel V, Kindschi G, Zohar Y (2001) Visualizing normal and defective bone development in zebrafish embryos using the fluorescent chromophore calcein. Dev Biol 238(2):239–246

    Article  CAS  PubMed  Google Scholar 

  21. Westerfield M (2000) The zebrafish book. University of Oregon Press, Eugene

    Google Scholar 

  22. Walker MB, Kimmel CB (2007) A two-color acid-free cartilage and bone stain for zebrafish larvae. Biotech Histochem 82(1):23–28

    CAS  PubMed  Google Scholar 

  23. Weber DN (2006) Dose-dependent effects of developmental mercury exposure on C-start escape responses of larval zebrafish Danio rerio. J Fish Biol 69:75–94

    Article  CAS  Google Scholar 

  24. Li ZX, Chen JW, Yuan F, Huang YY, Zhao LY, Li J, Su HX, Liu J, Pang JY, Lin YC, Lu XL, Pei Z, Wang GL, Guan YY (2013) Xyloketal B exhibits its antioxidant activity through induction of HO-1 in vascular endothelial cells and zebrafish. Mar Drugs 11(2):504–522

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Kalpatthi R, Peters B, Kane I, Holloman D, Rackoff E, Disco D, Jackson S, Laver JH, Abboud MR (2010) Safety and efficacy of high dose intravenous desferrioxamine for reduction of iron overload in sickle cell disease. Pediatr Blood Cancer 55(7):1338–1342

    Article  PubMed  Google Scholar 

  26. MacKenzie EL, Iwasaki K, Tsuji Y (2008) Intracellular iron transport and storage: from molecular mechanisms to health implications. Antioxid Redox Signal 10(6):997–1030

    Article  CAS  PubMed  Google Scholar 

  27. Huang J, Jones D, Luo B, Sanderson M, Soto J, Abel ED, Cooksey RC, McClain DA (2011) Iron overload and diabetes risk: a shift from glucose to fatty acid oxidation and increased hepatic glucose production in a mouse model of hereditary hemochromatosis. Diabetes 60(1):80–87

    Article  CAS  PubMed  Google Scholar 

  28. Salvador GA (2010) Iron in neuronal function and dysfunction. BioFactors 36(2):103–110

    Article  CAS  PubMed  Google Scholar 

  29. Murphy CJ, Oudit GY (2010) Iron-overload cardiomyopathy: pathophysiology, diagnosis, and treatment. J Cardiac Fail 16(11):888–900

    Article  CAS  Google Scholar 

  30. Jian J, Pelle E, Huang X (2009) Iron and menopause: Does increased iron affect the health of postmenopausal women? Antioxid Redox Signal 11(12):2939–2943

    Article  CAS  PubMed  Google Scholar 

  31. Barrett R, Chappell C, Quick M, Fleming A (2006) A rapid, high content, in vivo model of glucocorticoid-induced osteoporosis. Biotechnol J 1(6):651–655

    Article  CAS  PubMed  Google Scholar 

  32. Javed M, Saeed MA (2010) Growth and bioaccumulation of iron in the body organs of Catla catla, Labeo rohita and Cirrhina mrigala during chronic exposures. Int J Agric Biol 12:881–886

    Google Scholar 

  33. Yang Q, Jian J, Abramson SB, Huang X (2011) Inhibitory effects of iron on bone morphogenetic protein 2–induced osteoblastogenesis. J Bone Miner Res 26(6):1188–1196

    Article  CAS  PubMed  Google Scholar 

  34. Witten PE, Hansen A, Hall BK (2001) Features of mono- and multinucleated bone resorbing cells of the zebrafish Danio rerio and their contribution to skeletal development, remodeling, and growth. J Morphol 250(3):197–207

    Article  CAS  PubMed  Google Scholar 

  35. 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(2):292–296

    Article  CAS  PubMed  Google Scholar 

  36. Kehrer JP (2000) The Haber–Weiss reaction and mechanisms of toxicity. Toxicology 149(1):43–50

    CAS  PubMed  Google Scholar 

  37. Liu G, Men P, Kenner GH, Miller SC (2006) Age-associated iron accumulation in bone: implications for postmenopausal osteoporosis and a new target for prevention and treatment by chelation. Biometals 19(3):245–251

    Article  CAS  PubMed  Google Scholar 

  38. Liu G, Men P, Kenner GH, Miller SC (2008) Therapeutic effects of an oral chelator targeting skeletal tissue damage in experimental postmenopausal osteoporosis in rats. Hemoglobin 32(1–2):181–190

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by the National Natural Science Foundation of China (81273090), a Jiangsu Provincial Grant (BK2012608), Science and Technology Projects of Suzhou (SS201327), and the Foundation Program of Suzhou Key Laboratory of High Technology (SZS201208). All institutional and national guidelines for the care and use of laboratory animals were followed.

Conflicts of interest

Bin Chen, Yi-Lin Yan, Chen Liu, Lin Bo, Guang-Fei Li, Han Wang, You-Jia Xu state that they have no conflicts of interest

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Authors and Affiliations

  1. Department of Orthopaedics, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, China

    Bin Chen, Chen Liu, Lin Bo, Guang-Fei Li & You-Jia Xu

  2. Institute of Neuroscience, University of Oregon, Eugene, OR, USA

    Yi-Lin Yan

  3. Center for Circadian Clock, Soochow University, Suzhou, China

    Han Wang

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  1. Bin Chen
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  2. Yi-Lin Yan
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  3. Chen Liu
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  5. Guang-Fei Li
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  6. Han Wang
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  7. You-Jia Xu
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Correspondence to You-Jia Xu.

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Chen, B., Yan, YL., Liu, C. et al. Therapeutic Effect of Deferoxamine on Iron Overload-Induced Inhibition of Osteogenesis in a Zebrafish Model. Calcif Tissue Int 94, 353–360 (2014). https://doi.org/10.1007/s00223-013-9817-4

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  • DOI: https://doi.org/10.1007/s00223-013-9817-4

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