Iron-enriched diet contributes to early onset of osteoporotic phenotype in a mouse model of hereditary hemochromatosis

Abstract

Osteoporosis is associated with chronic iron overload secondary to hereditary hemochromatosis (HH), but the causative mechanisms are incompletely understood. The main objective of this study was to investigate the role of dietary iron on osteoporosis, using as biological model the Hfe-KO mice, which have a systemic iron overload. We showed that these mice show an increased susceptibility for developing a bone loss phenotype compared to WT mice, which can be exacerbated by an iron rich diet. The dietary iron overload caused an increase in inflammation and iron incorporation within the trabecular bone in both WT and Hfe-KO mice. However, the osteoporotic phenotype was only evident in Hfe-KO mice fed the iron-enriched diet. This appeared to result from an imbalance between bone formation and bone resorption driven by iron toxicity associated to Hfe-KO and confirmed by a decrease in bone microarchitecture parameters (identified by micro-CT) and osteoblast number. These findings were supported by the observed downregulation of bone metabolism markers and upregulation of ferritin heavy polypeptide 1 (Fth1) and transferrin receptor-1 (Tfrc), which are associated with iron toxicity and bone loss phenotype. In WT mice the iron rich diet was not enough to promote a bone loss phenotype, essentially due to the concomitant depression of bone resorption observed in those animals. In conclusion the dietary challenge influences the development of osteoporosis in the HH mice model thus suggesting that the iron content in the diet may influence the osteoporotic phenotype in systemic iron overload conditions.

Impaired Bone Microarchitecture in Patients with Hereditary Hemochromatosis and Skeletal Complications

“…In animal studies with different iron overload mouse models, micro-CT analysis revealed trabecular [36] as well as cortical bone loss with an increase of non-mineralized matrix and a decrease of carbonate-to-mineral ratio in FTIRI analysis indicating osteomalacia and increased bone turnover [17]. Our HHC patients also showed a reduced mineralization of the cortical bone, i.e., low Ct and BMD values.…”

Metabolomics Coupled with Pathway Analysis Provides Insights into Sarco-Osteoporosis Metabolic Alterations and Estrogen Therapeutic Effects in Mice

“…The recovery in both arginine biosynthesis and BMD in the E2 group showed a sign of iron process revival, where a potential chance arose for the reconstruction of bone homeostasis. Under iron balanced circumstances, osteoblasts can be kept away from threats [ 66 ] and the osteoclasts number should decrease compared to the iron resorption unbalanced group [ 67 ].…”

VMP35 MNC, a novel iron-free supplement, enhances cytoprotection against anemia in human subjects: a novel hypothesis

“…During the transport, iron remains in the blood for a very short time. However, in more extreme cases, the iron accumulates in vital organs, which contributes to the development of several diseases including hepatic cirrhosis, hepatocarcinoma, cardiac cirrhosis, diabetes mellitus, osteoarthritis, osteoporosis, and non-genetic secondary hemochromatosis also known as ‘iron-overload anemia’, as blood iron levels can be initially low with accumulated tissue levels being too high (15). This is a major reason why blood tests can be inaccurate in determining IDA.…”

“…histidine), to prevent a remarkable lowering of blood pH. It is well known that a heme group is attached to four histidines, while the iron atom in heme binds to the four nitrogens in the center of the protoporphyrin ring (14, 15). Under this condition, iron is cleaved from the heme protein to release histidine.…”