Hepcidin Deficiency Undermines Bone Load-bearing Capacity Through Inducing Iron Overload

Osteoporosis is one of the leading disorders among aged people. Bone loss results from anumber of physiological alterations, such as estrogen decline and aging. Meanwhile, ironoverload has been recognized as a risk factor for bone loss. Systemic iron homeostasis isfundamentally governed by the hepcidin–ferroportin regulatory axis, where hepcidin is thekey regulator. Hepcidin deficiency could induce a few disorders, of which iron overload is themost representative phenotype. However, there was little investigation of the effects ofhepcidin deficiency on bone metabolism. To this end, we used the Hamp1/male mice tostudy bone metabolism under the setting of disordered iron homeostasis and the relativemechanisms. Male Hamp1/mice and wild type (WT) mice with the same geneticbackground were sacrificed at8weeks,18weeks and30weeks. Sera and organ specimensand tibias were collected. Finally, iron parameters and the biomechanical properties of thetibias were examined. Our results revealed that significant iron overload was induced inHamp1/mice. Serum iron level was increased by approximately25%and40%and50%inHamp1/mice relative to WT mice at8weeks,18weeks and30weeks (p<0.05), respectively.However, the serum iron level remained consistent in WT mice over the time course from8weeks to30weeks (P<0.05). What’s more, there was an increase of liver iron concentrationsin a time-dependent manner in Hamp1/mice relative to WT mice from8weeks to30weeks(p<0.05). Importantly, significant decreases of maximal loading and maximal bending stresswere found in Hamp1/mice relative to wild type (WT) mice. The maximal loading wassignificantly reduced by20%in Hamp1/mice at the age of18weeks (p<0.05); Morestrikingly, the maximal loading was further reduced approximately by50%when mice reached30week old. Similar to the changes of the maximal loading, the maximal bendingwas also declined in Hamp1/mice compared to WT mice at the ages of18weeks and30weeks, especially at30weeks (p<0.05). Moreover, there was only a slight decrease of serumosteocalcin in Hamp1/mice compared to that in WT mice at30weeks with no significantdifference (p>0.05). However, we found that the CTX-1concentration was increased byapproximately25%in Hamp1/mice compared to WT mice at8weeks and18weeks(p<0.05). Moreover the CTX-1concentration was further increased (by32%) in Hamp1/mice comparison to WT mice at30weeks (p<0.05). Therefore, hepcidin deficiency resultedin a marked reduction of bone load-bearing capacity likely through enhancing bone resorption,suggesting a direct correlation between hepcidin deficiency and bone loss. Targeting hepcidinor the pathway it modulates may thus represent a therapeutic for osteopenia or osteoporosis.