Hepcidin1 Knockout Mice Display Defects in Bone Microarchitecture and Changes of Bone Formation Markers

Abstract

Iron accumulation is a risk factor of osteoporosis; mechanisms leading to iron-related bone loss are not fully determined. We sought to better understand the effect of chronic iron accumulation on bone over the life span in a mouse model. Hepcidin1 knockout (Hepc1(-/-)) male mice and their littermate control wild type (WT) mice at 7 months old were used in this study. Serum iron and ferritin as well as iron contents in liver and femur were significantly increased in Hepc1(-/-) mice compared to WT mice. We found that Hepc1(-/-) mice had a phenotype of low bone mass and alteration of the bone microarchitecture, most likely caused by a decreased osteoblastic activity. Cell culture studies indicated that chronic iron accumulation decreased bone formation, probably by affecting bone morphogenetic protein signaling.

Hepcidin is an endogenous protective factor for osteoporosis by reducing iron levels

“…Hepcidin is an iron-reducing parahormone that is synthesized in and secreted by the liver and a key regulator of iron homeostasis in vivo (Zhao et al 2013, Qian et al 2015. We hypothesize that hepcidin is an intrinsic protective factor against osteoporosis, and previous studies by us and others have shown that hepcidin deficiencies impair osteoblast function in zebrafish and mice, inhibit bone formation and decrease bone mass (Shen et al 2014, Sun et al 2014, Huang 2015. Few studies have investigated the effects of hepcidin overexpression on bone mass in mice, and in this study, we examined the effects of hepcidin on bone mass in murine hepcidin knockout and overexpression models.…”

“…After tamoxifen-induced hepcidin overexpression, serum hepcidin levels in Hamp OVX mice significantly increase, serum ferritin levels decrease and serum bone turnover markers CTX and CTK, and osteoclast-related marker genes Ptk2b, Mmo9, Ctsk and Trap, undergo downregulation. Hepcidin deficiency increases circulating iron levels in vivo and promotes bone loss in ovariectomized mice (Shen et al 2014, Sun et al 2014). Furthermore, hepcidin overexpression reduces circulating iron levels and retards bone loss, which coincide with Huang's hypothesis (Ma & Xu 2010, Kodama et al 2015, Jiang et al 2016.…”

“…Our previous studies have found that serum ferritin and liver iron contents were significantly higher in hepcidin-knockout mice than in wild-type mice. In hepcidin-knockout mice, the BMP/Smad pathway was also repressed, resulting in decreased osteoblast function and bone mass (Shen et al 2014).…”

Effects of dietary resveratrol on excess-iron-induced bone loss via antioxidative character

“…The femurs were placed with gauze in the sample holder and were scanned using the GE Healthcare Locus SP micro-CT (GE Healthcare, USA) using a resolution of 6 μm, 80 kV, 80 μA, 400 number of views and exposure of 5 h [19]. The explore reconstruction utility software (GE Healthcare, USA) was used for three-dimensional reconstruction and data processing.…”

Adverse Impact of Heavy Metals on Bone Cells and Bone Metabolism Dependently and Independently through Anemia

“…Promoted post-traumatic inflammation and impaired angiogenesis owing to a lack of EPO-inhibited NF-B signaling pathway, EPO-promoted VEGF expression and peripheral endothelial progenitor cells [ 109,110] Iron deficiency Stress erythropoiesis regulated by HRI-eIF2 P-ATF4 signaling pathway [92,94,[113][114][115] Decreased cortical width of femur and tibia, reduced mineralized skeleton, pathological modulation of microarchitecture in the vertebral trabecular bone, and reduced bone formation [ 116,117] Iron overload Iron deposits in bone and low circulating IGF-1 levels, resulting in impaired bone matrix maturation and defective mineralization [ 120] Impaired BMP signaling pathway related to hepcidin expression [ 121,125] Inhibition of osteoblast activity by ROS-activated NF-B signaling pathway [ 123,125] Inhibited osteoblast proliferation, enhanced osteoblast apoptosis and induction of oxidative stress via downregulation of miR-455-3p and upregulation of HDAC2-Nrf2/ARE [ 124] DMT-1 overexpression-mediated autophagy and apoptosis of osteoblasts [ 126] Stimulated differentiation of osteoclasts by ROS-activated NF-B signaling pathway [ 123] epidemiological evidence has proven the increased risks of both degenerative bone diseases and anemia induced by heavy metals. Additionally, anemia-promoted degenerative bone diseases have been established.…”