Differences in bone microarchitecture between genetic and secondary iron-overload mouse models suggest a role for hepcidin deficiency in iron-related osteoporosis

被引:3
作者
Robin, Francois [1 ,8 ]
Chappard, Daniel [2 ]
Leroyer, Patricia [1 ]
Latour, Chloe [3 ]
Mabilleau, Guillaume [4 ]
Monbet, Valerie [5 ]
Cavey, Thibault [1 ]
Horeau, Mathieu [1 ,6 ]
Derbre, Frederic [6 ]
Roth, Marie-Paule [3 ]
Ropert, Martine [1 ,7 ]
Guggenbuhl, Pascal [1 ]
Loreal, Olivier [1 ,7 ]
机构
[1] Univ Rennes, Inst NuMeCan Nutr Metab & Canc, INSERM, INRAE,CHU Rennes,U1241, Rennes, France
[2] IRIS IBS Biol Inst, GEROM, LHEA, Angers, France
[3] Univ Toulouse, IRSD, INSERM, INRAE,ENVT,UPS, Toulouse, France
[4] Univ Angers, Nantes Univ, Oniris, Inserm,RMeS,REGOS,SFR ICAT, Angers, France
[5] Univ Rennes, IRMAR, UMR 6625, Rennes, France
[6] Univ Rennes, ENS Rennes, Lab Movement Sport & Hlth Sci EA7470, Rennes, France
[7] Univ Rennes, Univ Hosp, Platform AEM2, Rennes, France
[8] Univ Rennes, Inst NuMeCan Nutrit Metab & Canc, INSERM, INRAE,CHU Rennes,U1241, 16 Blvd Bulgarie, F-35200 Rennes, France
关键词
bone QCT/mu CT; genetic animal models; hemochromatosis; iron overload; osteoporosis; MINERAL DENSITY; EXPRESSION; HEMOCHROMATOSIS; BMP6;
D O I
10.1096/fj.202301184R
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Iron overload is one of the secondary osteoporosis etiologies. Cellular and molecular mechanisms involved in iron-related osteoporosis are not fully understood.Aim: The aim of the study was to investigate the respective roles of iron excess and hepcidin, the systemic iron regulator, in the development of iron-related osteoporosis.Material and Methods: We used mice models with genetic iron overload (GIO) related to hepcidin deficiency (Hfe(-/-) and Bmp6(-/-)) and secondary iron overload (SIO) exhibiting a hepcidin increase secondary to iron excess. Iron concentration and transferrin saturation levels were evaluated in serum and hepatic, spleen, and bone iron concentrations were assessed by ICP-MS and Perl's staining. Gene expression was evaluated by quantitative RT-PCR. Bone micro-architecture was evaluated by micro-CT. The osteoblastic MC3T3 murine cells that are able to mineralize were exposed to iron and/or hepcidin.Results: Despite an increase of bone iron concentration in all overloaded mice models, bone volume/total volume (BV/TV) and trabecular thickness (Tb.Th) only decreased significantly in GIO, at 12 months for Hfe(-/-) and from 6 months for Bmp6(-/-). Alterations in bone microarchitecture in the Bmp6(-/-) model were positively correlated with hepcidin levels (BV/TV (rho = +.481, p < .05) and Tb.Th (rho = +.690, p < .05). Iron deposits were detected in the bone trabeculae of Hfe(-/-) and Bmp6(-/-) mice, while iron deposits were mainly visible in bone marrow macrophages in secondary iron overload. In cell cultures, ferric ammonium citrate exposure abolished the mineralization process for concentrations above 5 mu M, with a parallel decrease in osteocalcin, collagen 1, and alkaline phosphatase mRNA levels. Hepcidin supplementation of cells had a rescue effect on the collagen 1 and alkaline phosphatase expression level decrease.Conclusion: Together, these data suggest that iron in excess alone is not sufficient to induce osteoporosis and that low hepcidin levels also contribute to the development of osteoporosis.
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页数:16
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