Hepcidin deficiency undermines bone load-bearing capacity through inducing iron overload

Abstract

Osteoporosis is one of the leading disorders among aged people. Bone loss results from a number of physiological alterations, such as estrogen decline and aging. Meanwhile, iron overload has been recognized as a risk factor for bone loss. Systemic iron homeostasis is fundamentally governed by the hepcidin-ferroportin regulatory axis, where hepcidin is the key regulator. Hepcidin deficiency could induce a few disorders, of which iron overload is the most representative phenotype. However, there was little investigation of the effects of hepcidin deficiency on bone metabolism. To this end, hepcidin-deficient (Hamp1 −/− ) mice were employed to address this issue. Our results revealed that significant iron overload was induced in Hamp1 −/− mice. Importantly, significant decreases of maximal loading and maximal bending stress were found in Hamp1 −/− mice relative to wildtype (WT) mice.Moreover, the levels of the C-telopeptide of type I collagen (CTX-1) increased in Hamp1 −/− mice. Therefore, hepcidin deficiency resulted in a marked reduction of bone load-bearing capacity likely through enhancing bone resorption, suggesting a direct correlation between hepcidin deficiency and bone loss. Targeting hepcidin or the pathway it modulates may thus represent a therapeutic for osteopenia or osteoporosis.

Iron overload inhibits osteogenic commitment and differentiation of mesenchymal stem cells via the induction of ferritin

“…Recently in a prospective cross-sectional study on 80 patients with beta thalassemia major and intermedia, the authors found that both serum ferritin and heart iron load were negatively correlated with bone mineral density [37]. Animal models of iron overload also supported the deleterious effect of excess iron on bone mineral density [12][13][14]16,38,39].…”

“…Additionally, we evaluated whether iron inhibits osteogenic mixture-induced increase of ALP activity. Osteogenic mixture consisted of dexamethasone, ascorbic acid and β-glycerolphosphate induced a marked elevation of ALP activity (4.76 ± 0.36 vs. 16.59 ± 1.69 unit/mg protein) in BMSCs. Increase of ALP activity triggered by osteogenic mixture was reduced by about 40% in the presence of iron (Fig.…”

“…Recently, hepcidin, the liver-derived regulator of iron homeostasis has been also identified as a factor influencing bone physiology. Lack of hepcidin triggers severe tissue iron overload that is associated with low bone mass, and altered bone microarchitecture [15,16].…”

Reduced hepcidin level features osteoporosis

“…Hepcidin has been suggested to have anti-osteoporosis effects by preventing iron overload (17), suggesting that the level of hepcidin seems to be inversed with level of iron accumulation. Sun et al (18) confirmed the in vivo use of a transgenic mouse model. In addition, the relevant studies performed concerning hepcidin in osteoporosis were either from in vitro cell culture system or in vivo animal models.…”

Spongious therapy of iron overload with hipcidin overexpressed macrophages

“…Then, in the presence of the human serum for 7-10 days, the monocytes are differentiated to the macrophages [11] . It has been already found that the hipcidin hormone inhibits iron transport out of macrophages by inducing ferroportin internalization and degradation [12,13] . So, upon overexpression of hipcidin in macrophages, these manipulated cells are able to absorb iron greater than normal level.…”