title: Decreased Bone Formation Explains Osteoporosis in a Genetic Mouse Model of Hemochromatosiss.
abstract: Osteoporosis may complicate iron overload diseases such as genetic hemochromatosis. However, molecular mechanisms involved in the iron-related osteoporosis remains poorly understood. Recent in vitro studies support a role of osteoblast impairment in iron-related osteoporosis. Our aim was to analyse the impact of excess iron in Hfe-/- mice on osteoblast activity and on bone microarchitecture. We studied the bone formation rate, a dynamic parameter reflecting osteoblast activity, and the bone phenotype of Hfe-/- male mice, a mouse model of human hemochromatosis, by using histomorphometry. Hfe-/- animals were sacrificed at 6 months and compared to controls. We found that bone contains excess iron associated with increased hepatic iron concentration in Hfe-/- mice. We have shown that animals with iron overload have decreased bone formation rate, suggesting a direct impact of iron excess on active osteoblasts number. For bone mass parameters, we showed that iron deposition was associated with bone loss by producing microarchitectural impairment with a decreased tendency in bone trabecular volume and trabecular number. A disorganization of trabecular network was found with marrow spaces increased, which was confirmed by enhanced trabecular separation and star volume of marrow spaces. These microarchitectural changes led to a loss of connectivity and complexity in the trabecular network, which was confirmed by decreased interconnectivity index and increased Minkowski's fractal dimension. Our results suggest for the first time in a genetic hemochromatosis mouse model, that iron overload decreases bone formation and leads to alterations in bone mass and microarchitecture. These observations support a negative effect of iron on osteoblast recruitment and/or function, which may contribute to iron-related osteoporosis.
authors.affiliation: INSERM UMR U991, F- 35033, Rennes, France.|Université de Rennes 1, IFR 140, F- 35043, Rennes, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Doyard
authors.affiliation: GEROM Groupe Etude Remodelage Osseux et bioMatériaux LHEA, IRIS-IBM, Institut de biologie en santé, CHU, F- 49933, Angers, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chappard
authors.affiliation: INSERM UMR U991, F- 35033, Rennes, France.|Université de Rennes 1, IFR 140, F- 35043, Rennes, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Leroyer
authors.affiliation: INSERM U1043, F- 31300, Toulouse, France.
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Roth
authors.affiliation: INSERM UMR U991, F- 35033, Rennes, France.|Université de Rennes 1, IFR 140, F- 35043, Rennes, France.|Service des Maladies du Foie, Hôpital Pontchaillou, CHU, F- 35033, Rennes, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Loréal
authors.affiliation: INSERM UMR U991, F- 35033, Rennes, France.|Université de Rennes 1, IFR 140, F- 35043, Rennes, France.|Service de Rhumatologie, Hôpital Sud, CHU, F- 35033, Rennes, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Guggenbuhl
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology*; D002113:Calcification, Physiologic; D004195:Disease Models, Animal; D006432:Hemochromatosis / Q000150:complications* / Q000235:genetics* / Q000378:metabolism; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010012:Osteogenesis; D010024:Osteoporosis / Q000209:etiology* / Q000473:pathology*
chemical_list: D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D007501:Iron
references.citation: Microsc Res Tech. 1999 May 15-Jun 1;45(4-5):303-12
references.pmid: 10383123
references.citation: Osteoporos Int. 2012 Oct;23(10):2435-45
references.pmid: 22237814
references.citation: J Clin Endocrinol Metab. 2005 Apr;90(4):2451-5
references.pmid: 15657376
references.citation: Transfus Clin Biol. 2005 Jun;12(2):77-82
references.pmid: 15925529
references.citation: Nat Clin Pract Gastroenterol Hepatol. 2004 Nov;1(1):39-45
references.pmid: 16265043
references.citation: Ann N Y Acad Sci. 2005;1054:462-6
references.pmid: 16339698
references.citation: Bone. 2006 Apr;38(4):571-5
references.pmid: 16298178
references.citation: J Bone Miner Metab. 2007;25(1):60-7
references.pmid: 17187195
references.citation: Indian Pediatr. 2007 Jan;44(1):29-32
references.pmid: 17277428
references.citation: Calcif Tissue Int. 2007 Feb;80(2):97-102
references.pmid: 17308991
references.citation: Pediatr Hematol Oncol. 2007 Oct-Nov;24(7):469-79
references.pmid: 17786783
references.citation: Toxicol Pathol. 2001 Nov-Dec;29(6):623-9
references.pmid: 11794378
references.citation: Clin Endocrinol (Oxf). 2003 Mar;58(3):273-9
references.pmid: 12608931
references.citation: J Clin Endocrinol Metab. 2003 Aug;88(8):3966-72
references.pmid: 12915694
references.citation: J Bone Miner Res. 2004 May;19(5):722-7
references.pmid: 15068494
references.citation: Lancet. 1971 Jan 16;1(7690):100-3
references.pmid: 4099600
references.citation: Rev Rhum Mal Osteoartic. 1979 Feb;46(2):91-9
references.pmid: 432519
references.citation: Am J Pathol. 1984 Sep;116(3):377-84
references.pmid: 6476075
references.citation: Am J Gastroenterol. 1989 Oct;84(10):1231-4
references.pmid: 2801672
references.citation: Am J Med. 1993 Jun;94(6):646-50
references.pmid: 8506892
references.citation: J Rheumatol. 1997 Sep;24(9):1809-13
references.pmid: 9292808
references.citation: Ann N Y Acad Sci. 1998 Jun 30;850:344-8
references.pmid: 9668556
references.citation: Br J Haematol. 1998 Dec;103(4):911-5
references.pmid: 9886300
references.citation: Nature. 1999 Feb 18;397(6720):617-21
references.pmid: 10050855
references.citation: J Pediatr Endocrinol Metab. 1998;11 Suppl 3:975-7
references.pmid: 10091176
references.citation: Toxicology. 2008 Apr 18;246(2-3):143-7
references.pmid: 18289763
references.citation: Metabolism. 2008 Jul;57(7):903-10
references.pmid: 18555830
references.citation: Skeletal Radiol. 2008 Jun;37(6):541-8
references.pmid: 18327577
references.citation: J Bone Miner Res. 2009 Mar;24(3):543-57
references.pmid: 18505376
references.citation: Osteoporos Int. 2009 Apr;20(4):549-55
references.pmid: 18661088
references.citation: Pediatr Endocrinol Rev. 2008 Oct;6 Suppl 1:107-15
references.pmid: 19337163
references.citation: Stem Cells. 2009 Mar;27(3):703-13
references.pmid: 19096040
references.citation: Bone. 2009 Nov;45(5):972-9
references.pmid: 19643212
references.citation: Toxicol Lett. 2009 Dec 15;191(2-3):211-5
references.pmid: 19735707
references.citation: Antioxid Redox Signal. 2009 Dec;11(12):2939-43
references.pmid: 19527179
references.citation: Joint Bone Spine. 2009 Dec;76(6):595-601
references.pmid: 19926512
references.citation: Pathol Biol (Paris). 2010 Oct;58(5):316-23
references.pmid: 19942367
references.citation: Blood. 2010 Oct 7;116(14):2582-9
references.pmid: 20554970
references.citation: J Bone Miner Res. 2011 Jun;26(6):1188-96
references.pmid: 21308772
references.citation: Osteoporos Int. 2011 Aug;22(8):2313-9
references.pmid: 20976594
references.citation: Best Pract Res Clin Rheumatol. 2011 Oct;25(5):649-64
references.pmid: 22142745
references.citation: J Cell Biochem. 2012 Jan;113(1):204-8
references.pmid: 21898541
references.citation: Eur J Haematol. 2005 Apr;74(4):359-61
references.pmid: 15777350