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Iron homeostasis in osteoporosis and its clinical implications

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Abstract

Osteoporosis has until now been considered to be a disease associated with abnormal calcium metabolism. However, an increasing number of clinical observations strongly suggest the association of iron overload with bone diseases, particularly in osteoporosis in menopausal women. The recent identification of hepcidin sheds new light into the crucial role of iron homeostasis in bone metabolism. Decreasing iron overload in cell studies as well as in animal experiments has been shown to improve bone cell metabolism and growth in vitro and in vivo. In view of the significant iron overload found in the aging population, especially in females, the therapeutic potential of lowering iron overload for the treatment of osteoporosis is suggested.

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References

  1. Delbarre F (1960) Osteoporosis in hemochromatosis. Sem Hop 36:3279–3294

    PubMed  CAS  Google Scholar 

  2. Delbarre F (1964) Osteoarticular manifestations of hemochromatosis. Presse Med 72:2973–2978

    PubMed  CAS  Google Scholar 

  3. Duquenne M, Rohmer V, Legrand E, Chappard D, Wion Barbot N, Basle MF, Audran M, Bigorgne JC (1996) Spontaneous multiple vertebral fractures revealed primary haemochromatosis. Osteoporos Int 6(4):338–340

    Article  PubMed  CAS  Google Scholar 

  4. Eyres KS, McCloskey EV, Fern ED, Rogers S, Beneton M, Aaron JE, Kanis JA (1992) Osteoporotic fractures: an unusual presentation of haemochromatosis. Bone 13(6):431–433

    Article  PubMed  CAS  Google Scholar 

  5. Kagan IE, Settarova DA, Tokarev IuN, Burdina LM (1989) Roentgenologic studies of changes of the osteoarticular system in patients with hereditary hemochromatosis. Gematol Transfuziol 34(10):19–24

    PubMed  CAS  Google Scholar 

  6. Sella EJ, Goodman AH (1973) Arthropathy secondary to transfusion hemochromatosis. J Bone Joint Surg Am 55(5):1077–1081

    PubMed  CAS  Google Scholar 

  7. Wardle EN, Patton JT (1969) Bone and joint changes in haemochromatosis. Ann Rheum Dis 28(1):15–23

    Article  PubMed  CAS  Google Scholar 

  8. Nicolino J, Lucciani JM (1967) Apropos of osteoarthropathies in idiopathic hemochromatoses. Diabete 15(3):196–200

    PubMed  CAS  Google Scholar 

  9. Du Lac Y, Deloux G, Deuil R (1967) Arthropathies and chondrocalcinosis during hemochromatosis. Rev Rhum Mal Osteoartic 34(12):758–769

    PubMed  Google Scholar 

  10. Dorfmann H, Solnica J, Mitrovic D, Dreyfus P (1969) Changes of bones and joints in hemochromatosis. Munch Med Wochenschr 111(25):1396–1401

    PubMed  CAS  Google Scholar 

  11. Lynch SR, Seftel HC, Wapnick AA, Charlton RW, Bothwell TH (1970) Some aspects of calcium metabolism in normal and osteoporotic Bantu subjects with special reference to the effects of iron overload and ascorbic acid depletion. S Afr J Med Sci 35(2):45–56

    PubMed  CAS  Google Scholar 

  12. de Seze S, Solnica J, Mitrovic D, Miravet L, Dorfmann H (1972) Joint and bone disorders and hypoparathyroidism in hemochromatosis. Semin Arthritis Rheum 2(1):71–94

    Article  PubMed  Google Scholar 

  13. Sabando P, Miravet L, Dorfman H, Kahn MF, Tun Chot S, Bordier P, Hioco D, De Seze S (1973) The osteopathy of hemochromatosis. Clinical and biological study. Rev Clin Esp 129(6):545–550

    PubMed  CAS  Google Scholar 

  14. Urbina B, de Miguel Mendieta E, Gijon-Banos JG (1983) Joint disease in idiopathic hemochromatosis. Rev Rhum Mal Osteoartic 50(8–9):585–587

    PubMed  CAS  Google Scholar 

  15. Diamond T, Stiel D, Posen S (1989) Osteoporosis in hemochromatosis: iron excess, gonadal deficiency, or other factors? Ann Intern Med 110(6):430–436

    PubMed  CAS  Google Scholar 

  16. Conte D, Caraceni MP, Duriez J, Mandelli C, Corghi E, Cesana M, Ortolani S, Bianchi PA (1989) Bone involvement in primary hemochromatosis and alcoholic cirrhosis. Am J Gastroenterol 84(10):1231–1234

    PubMed  CAS  Google Scholar 

  17. Axford JS (1991) Rheumatic manifestations of haemochromatosis. Baillieres Clin Rheumatol 5(2):351–365

    Article  PubMed  CAS  Google Scholar 

  18. Sinigaglia L, Fargion S, Fracanzani AL, Binelli L, Battafarano N, Varenna M, Piperno A, Fiorelli G (1997) Bone and joint involvement in genetic hemochromatosis: role of cirrhosis and iron overload. J Rheumatol 24(9):1809–1813

    PubMed  CAS  Google Scholar 

  19. Zeevaert B, Crielaard JM (1999) Osteoarticular hemochromatosis. Rev Med Liege 54(3):169–174

    PubMed  CAS  Google Scholar 

  20. Vaiopoulos G, Papanikolaou G, Politou M, Jibreel I, Sakellaropoulos N, Loukopoulos D (2003) Arthropathy in juvenile hemochromatosis. Arthritis Rheum 48(1):227–230

    Article  PubMed  Google Scholar 

  21. Rollot F, Wechsler B, du Boutin le TH, De Gennes C, Amoura Z, Hachulla E, Piette JC (2005) Hemochromatosis and femoral head aseptic osteonecrosis: a nonfortuitous association? J Rheumatol 32(2):376–378

    PubMed  Google Scholar 

  22. 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  PubMed  CAS  Google Scholar 

  23. Chales G, Guggenbuhl P, Pawlotsky Y (2006) Iron overload and arthropathy. Rev Prat 56(19):2135–2140

    PubMed  Google Scholar 

  24. Valenti L, Varenna M, Fracanzani AL, Rossi V, Fargion S, Sinigaglia L (2009) Association between iron overload and osteoporosis in patients with hereditary hemochromatosis. Osteoporos Int 20(4):549–555

    Article  PubMed  CAS  Google Scholar 

  25. Richette P, Ottaviani S, Vicaut E, Bardin T (2010) Musculoskeletal complications of hereditary hemochromatosis: a case–control study. J Rheumatol 37(10):2145–2150

    Article  PubMed  Google Scholar 

  26. Guggenbuhl P, Fergelot P, Doyard M, Libouban H, Roth MP, Gallois Y, Chales G, Loreal O, Chappard D (2011) Bone status in a mouse model of genetic hemochromatosis. Osteoporos Int 22(8):2313–2319

    Article  PubMed  CAS  Google Scholar 

  27. Guggenbuhl P, Brissot P, Loreal O (2011) Haemochromatosis: the bone and the joint. Best Pract Res Clin Rheumatol 25(5):649–664

    Article  PubMed  Google Scholar 

  28. 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

    PubMed  CAS  Google Scholar 

  29. Schnitzler CM, Macphail AP, Shires R, Schnaid E, Mesquita JM, Robson HJ (1994) Osteoporosis in African hemosiderosis: role of alcohol and iron. J Bone Miner Res 9(12):1865–1873

    Article  PubMed  CAS  Google Scholar 

  30. Schnitzler CM, Schnaid E, MacPhail AP, Mesquita JM, Robson HJ (2005) Ascorbic acid deficiency, iron overload and alcohol abuse underlie the severe osteoporosis in black African patients with hip fractures—a bone histomorphometric study. Calcif Tissue Int 76(2):79–89

    Article  PubMed  CAS  Google Scholar 

  31. Rioja L, Girot R, Garabedian M, Cournot-Witmer G (1990) Bone disease in children with homozygous beta-thalassemia. Bone Miner 8(1):69–86

    Article  PubMed  CAS  Google Scholar 

  32. Mahachoklertwattana P, Sirikulchayanonta V, Chuansumrit A, Karnsombat P, Choubtum L, Sriphrapradang A, Domrongkitchaiporn S, Sirisriro R, Rajatanavin R (2003) Bone histomorphometry in children and adolescents with beta-thalassemia disease: iron-associated focal osteomalacia. J Clin Endocrinol Metab 88(8):3966–3972

    Article  PubMed  CAS  Google Scholar 

  33. Voskaridou E, Terpos E (2004) New insights into the pathophysiology and management of osteoporosis in patients with beta thalassaemia. Br J Haematol 127(2):127–139

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  35. Haidar R, Mhaidli H, Musallam K, Taher AT (2012) The spine in beta thalassemia syndromes. Spine (Phila Pa 1976) 37(4):334–339

    Article  Google Scholar 

  36. 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  PubMed  CAS  Google Scholar 

  37. Sadat-Ali M, Sultan O, Al-Turki H, Alelq A (2011) Does high serum iron level induce low bone mass in sickle cell anemia? Biometals 24(1):19–22

    Article  PubMed  CAS  Google Scholar 

  38. Wibaux C, Legroux-Gerot I, Dharancy S, Boleslawski E, Declerck N, Canva V, Mathurin P, Pruvot FR, Cortet B (2011) Assessing bone status in patients awaiting liver transplantation. Joint Bone Spine 78(4):387–391

    Article  PubMed  Google Scholar 

  39. Topcheeva ON (2010) Hepatic osteodystrophy in patients with liver cirrhosis. Eksp Klin Gastroenterol 6:89–94

    PubMed  Google Scholar 

  40. Loria I, Albanese C, Giusto M, Galtieri PA, Giannelli V, Lucidi C, Di Menna S, Pirazzi C, Corradini SG, Mennini G, Rossi M, Berloco P, Merli M (2010) Bone disorders in patients with chronic liver disease awaiting liver transplantation. Transplant Proc 42(4):1191–1193

    Article  PubMed  CAS  Google Scholar 

  41. Goral V, Simsek M, Mete N (2010) Hepatic osteodystrophy and liver cirrhosis. World J Gastroenterol 16(13):1639–1643

    Article  PubMed  CAS  Google Scholar 

  42. Smith DL, Shire NJ, Watts NB, Schmitter T, Szabo G, Zucker SD (2006) Hyperbilirubinemia is not a major contributing factor to altered bone mineral density in patients with chronic liver disease. J Clin Densitom 9(1):105–113

    Article  PubMed  Google Scholar 

  43. Diamond T, Stiel D, Lunzer M, Wilkinson M, Roche J, Posen S (1990) Osteoporosis and skeletal fractures in chronic liver disease. Gut 31(1):82–87

    Article  PubMed  CAS  Google Scholar 

  44. Long RG, Meinhard E, Skinner RK, Varghese Z, Wills MR, Sherlock S (1978) Clinical, biochemical, and histological studies of osteomalacia, osteoporosis, and parathyroid function in chronic liver disease. Gut 19(2):85–90

    Article  PubMed  CAS  Google Scholar 

  45. Park CH, Valore EV, Waring AJ, Ganz T (2001) Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 276(11):7806–7810

    Article  PubMed  CAS  Google Scholar 

  46. Youjia Xu, Pierre Sirois, Kai Li (2010) Iron overload plays a unique role in osteoporosis. [E-letter] Blood (9 Sep 2010). http://bloodjournal.hematologylibrary.org/content/116/14/2582.full/reply#bloodjournal_el_524. Accessed 9 Sep 2010

  47. Xi Huang (2010) Treatment of osteoporosis in peri- and post-menopausal women with hepcidin. United States Patent Application Publication, Pub. No.: US 2010/0204122 A1

  48. Xu Y, Li G, Du B, Zhang P, Xiao L, Sirois P, Li K (2011) Hepcidin increases intracellular Ca2+ of osteoblast hFOB1.19 through L-type Ca2+ channels. Regul Pept 172(1–3):58–61

    Article  PubMed  CAS  Google Scholar 

  49. Xu Y, Zhang W, Zhang P, Xiao L, Wang A, Sirois P, Li K (2012) Downregulation of ferroportin 1 expression in hFOB1.19 osteoblasts by hepcidin. Inflammation. doi:10.1007/s10753-011-9411-8

  50. Merono T, Sorroche P, Brites FD (2011) Increased iron store and its relationship with cardiovascular disease. Medicina (B Aires) 71(6):566–572

    Google Scholar 

  51. Sipe JC, Lee P, Beutler E (2002) Brain iron metabolism and neurodegenerative disorders. Dev Neurosci 24(2–3):188–196

    Article  PubMed  CAS  Google Scholar 

  52. Aamodt AH, Stovner LJ, Thorstensen K, Lydersen S, White LR, Aasly JO (2007) Prevalence of haemochromatosis gene mutations in Parkinson’s disease. J Neurol Neurosurg Psychiatry 78(3):315–317

    Article  PubMed  Google Scholar 

  53. Gille G, Reichmann H (2011) Iron-dependent functions of mitochondria—relation to neurodegeneration. J Neural Transm 118(3):349–359

    Article  PubMed  CAS  Google Scholar 

  54. Guggenbuhl P, Filmon R, Mabilleau G, Basle MF, Chappard D (2008) Iron inhibits hydroxyapatite crystal growth in vitro. Metabolism 57(7):903–910

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  56. 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(1):164–172

    Article  PubMed  CAS  Google Scholar 

  57. Halliwell B, Gutteridge JM (1990) Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol 186:1–85

    Article  PubMed  CAS  Google Scholar 

  58. Fridovich I (1978) The biology of oxygen radicals. Science 201(4359):875–880

    Article  PubMed  CAS  Google Scholar 

  59. Almeida M, Han L, Martin-Millan M, O’Brien CA, Manolagas SC (2007) Oxidative stress antagonizes Wnt signaling in osteoblast precursors by diverting beta-catenin from T cell factor- to forkhead box O-mediated transcription. J Biol Chem 282(37):27298–27305

    Article  PubMed  CAS  Google Scholar 

  60. Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W (1996) Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 382(6592):638–642

    Article  PubMed  CAS  Google Scholar 

  61. Qu ZH, Zhang XL, Tang TT, Dai KR (2008) Promotion of osteogenesis through beta-catenin signaling by desferrioxamine. Biochem Biophys Res Commun 370(2):332–337

    Article  PubMed  CAS  Google Scholar 

  62. Ishii KA, Fumoto T, Iwai K, Takeshita S, Ito M, Shimohata N, Aburatani H, Taketani S, Lelliott CJ, Vidal-Puig A, Ikeda K (2009) Coordination of PGC-1beta and iron uptake in mitochondrial biogenesis and osteoclast activation. Nat Med 15(3):259–266

    Article  PubMed  CAS  Google Scholar 

  63. 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  PubMed  CAS  Google Scholar 

  64. Isomura H, Fujie K, Shibata K, Inoue N, Iizuka T, Takebe G, Takahashi K, Nishihira J, Izumi H, Sakamoto W (2004) Bone metabolism and oxidative stress in postmenopausal rats with iron overload. Toxicology 197(2):93–100

    Article  PubMed  CAS  Google Scholar 

  65. Kudo H, Suzuki S, Watanabe A, Kikuchi H, Sassa S, Sakamoto S (2008) Effects of colloidal iron overload on renal and hepatic siderosis and the femur in male rats. Toxicology 246(2–3):143–147

    Article  PubMed  CAS  Google Scholar 

  66. Morabito N, Russo GT, Gaudio A, Lasco A, Catalano A, Morini E, Franchina F, Maisano D, La Rosa M, Plota M, Crifo A, Meo A, Frisina N (2007) The “lively” cytokines network in beta-thalassemia major-related osteoporosis. Bone 40(6):1588–1594

    Article  PubMed  CAS  Google Scholar 

  67. 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  PubMed  CAS  Google Scholar 

  68. Krause A, Neitz S, Magert HJ, Schulz A, Forssmann WG, Schulz-Knappe P, Adermann K (2000) LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett 480(2–3):147–150

    Article  PubMed  CAS  Google Scholar 

  69. Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P, Loreal O (2001) A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 276(11):7811–7819

    Article  PubMed  CAS  Google Scholar 

  70. Nicolas G, Bennoun M, Devaux I, Beaumont C, Grandchamp B, Kahn A, Vaulont S (2001) Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci USA 98(15):8780–8785

    Article  PubMed  CAS  Google Scholar 

  71. Nicolas G, Bennoun M, Porteu A, Mativet S, Beaumont C, Grandchamp B, Sirito M, Sawadogo M, Kahn A, Vaulont S (2002) Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci USA 99(7):4596–4601

    Article  PubMed  CAS  Google Scholar 

  72. Fleming RE, Sly WS (2001) Hepcidin: a putative iron-regulatory hormone relevant to hereditary hemochromatosis and the anemia of chronic disease. Proc Natl Acad Sci USA 98(15):8160–8162

    Article  PubMed  CAS  Google Scholar 

  73. 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(5704):2090–2093

    Article  PubMed  CAS  Google Scholar 

  74. Nemeth E, Ganz T (2006) Regulation of iron metabolism by hepcidin. Annu Rev Nutr 26:323–342

    Article  PubMed  CAS  Google Scholar 

  75. Ganz T, Nemeth E (2006) Iron imports. IV. Hepcidin and regulation of body iron metabolism. Am J Physiol Gastrointest Liver Physiol 290(2):G199–G203

    Article  PubMed  CAS  Google Scholar 

  76. De Domenico I, Ward DM, Langelier C, Vaughn MB, Nemeth E, Sundquist WI, Ganz T, Musci G, Kaplan J (2007) The molecular mechanism of hepcidin-mediated ferroportin down-regulation. Mol Biol Cell 18(7):2569–2578

    Article  PubMed  Google Scholar 

  77. Rivera S, Nemeth E, Gabayan V, Lopez MA, Farshidi D, Ganz T (2005) Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs. Blood 106(6):2196–2199

    Article  PubMed  CAS  Google Scholar 

  78. Ma Y, Youjia Xu, Wang A et al (2006) A preliminary report of expression of hepcidin gene in SD rats osteoporosis model. Suzhou Univ J Med Sci 26:367–369

    CAS  Google Scholar 

  79. Zhang P, Xu YJ, Zhao DY, Ma Y, Xiao L, Feng YS, Du BC, Qian ZM, Li K (2010) Increased intracellular iron and mineralization of cultured hFOB 1.19 cells following hepcidin activation through ferroportin-1. Saudi Med J 31(12):1303–1308

    PubMed  Google Scholar 

  80. Ma Y, Xu Y (2010) Research on relationship between FPN1 content and effect of hepcidin on intracellular calcium and iron change in osteoblasts. Bone 47(1):406

    Article  Google Scholar 

  81. 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  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  83. Wu CH, Yang YC, Yao WJ, Lu FH, Wu JS, Chang CJ (2002) Epidemiological evidence of increased bone mineral density in habitual tea drinkers. Arch Intern Med 162(9):1001–1006

    Article  PubMed  Google Scholar 

  84. 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  PubMed  CAS  Google Scholar 

  85. Cornish J, Palmano K, Callon KE, Watson M, Lin JM, Valenti P, Naot D, Grey AB, Reid IR (2006) Lactoferrin and bone; structure–activity relationships. Biochem Cell Biol 84(3):297–302

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Orthopaedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China

    G. F. Li & Y. J. Xu

  2. Department of Molecular Diagnostics and Biopharmaceutics, College of Pharmacy, Soochow University, Suzhou, Jiangsu, China

    Y. Z. Pan & K. Li

  3. IPS Therapeutique Inc., Sherbrooke, QC, Canada, JIE 4K8

    P. Sirois

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  1. G. F. Li
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  2. Y. Z. Pan
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  3. P. Sirois
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  4. K. Li
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Correspondence to K. Li or Y. J. Xu.

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Li, G.F., Pan, Y.Z., Sirois, P. et al. Iron homeostasis in osteoporosis and its clinical implications. Osteoporos Int 23, 2403–2408 (2012). https://doi.org/10.1007/s00198-012-1982-1

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