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

Autor: Robin F; INSERM, Univ Rennes, INRAE, CHU Rennes, U 1241, Institut NuMeCan (Nutrition Metabolisms and Cancer), Rennes, France., Chappard D; GEROM, LHEA, IRIS-IBS Biology Institut, Angers cedex, France., Leroyer P; INSERM, Univ Rennes, INRAE, CHU Rennes, U 1241, Institut NuMeCan (Nutrition Metabolisms and Cancer), Rennes, France., Latour C; IRSD, Univ Toulouse, INSERM, INRAE, ENVT, UPS, Toulouse, France., Mabilleau G; Univ Angers, Nantes Université, Oniris, Inserm, RMeS, REGOS, SFR ICAT, Angers, France., Monbet V; Univ Rennes, IRMAR, UMR 6625, Rennes, France., Cavey T; INSERM, Univ Rennes, INRAE, CHU Rennes, U 1241, Institut NuMeCan (Nutrition Metabolisms and Cancer), Rennes, France., Horeau M; INSERM, Univ Rennes, INRAE, CHU Rennes, U 1241, Institut NuMeCan (Nutrition Metabolisms and Cancer), Rennes, France.; Laboratory 'Movement Sport and Health Sciences' EA7470, University of Rennes/ENS Rennes, Rennes, France., Derbré F; Laboratory 'Movement Sport and Health Sciences' EA7470, University of Rennes/ENS Rennes, Rennes, France., Roth MP; IRSD, Univ Toulouse, INSERM, INRAE, ENVT, UPS, Toulouse, France., Ropert M; INSERM, Univ Rennes, INRAE, CHU Rennes, U 1241, Institut NuMeCan (Nutrition Metabolisms and Cancer), Rennes, France.; AEM2 Platform, Univ Rennes, University Hospital, Rennes, France., Guggenbuhl P; INSERM, Univ Rennes, INRAE, CHU Rennes, U 1241, Institut NuMeCan (Nutrition Metabolisms and Cancer), Rennes, France., Loréal O; INSERM, Univ Rennes, INRAE, CHU Rennes, U 1241, Institut NuMeCan (Nutrition Metabolisms and Cancer), Rennes, France.; AEM2 Platform, Univ Rennes, University Hospital, Rennes, France.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2023 Nov; Vol. 37 (11), pp. e23245.
DOI: 10.1096/fj.202301184R
Abstrakt: 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 (ρ = +.481, p < .05) and Tb.Th (ρ = +.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 μM, 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.
(© 2023 Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
Externí odkaz: