Effects of Mouse Hepcidin 1 Treatment on Osteoclast Differentiation and Intracellular Iron Concentration
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Effects of Mouse Hepcidin 1 Treatment on Osteoclast Differentiation and Intracellular Iron Concentration Guo-yang Zhao,1 Dong-hua Di,1 Bo Wang,1 Xi Huang,3 and You-jia Xu2,4
Abstract—Hepcidin is a key player in the regulation of mammalian iron homeostasis. Because iron overload may be one of the causes of osteoporosis, hepcidin may have therapeutic potential for osteoporosis patients. However, the effects of hepcidin on bone metabolism are not fully clear. We recently found that hepcidin can increase intracellular iron and calcium levels and promote mineralization in osteoblasts. The present study was designed to evaluate the effects of hepcidin on osteoclasts. Our results showed that mouse hepcidin 1 (MH1) can increase the number of TRAP-positive MNCs concomitant in both bone marrow-derived macrophages (BMMs) and RAW264.7 cells and upregulate mRNA levels of TRAP, cathepsin K, and MMP-9 and increase TRAP-5b protein secretion in RAW264.7 cells. Moreover, MH1 can downregulate the level of FPN1 protein and increase intracellular iron in RAW 264.7 cells. Therefore, we conclude that MH1 can significantly facilitate osteoclast differentiation in vitro. The mechanism behind accelerated differentiation may be associated with increased levels of intracellular iron. These findings may facilitate understanding of the effects of hepcidin on bone metabolism. KEY WORDS: hepcidin; osteoclast; differentiation; bone metabolism.
may be one of the reasons for bone diseases, particularly osteoporosis in menopausal women [3–6]. In 2010, a patent application entitled “Treatment of osteoporosis in periand post-menopausal women with hepcidin” was published in the USA [7], which indicated that hepcidin may also have therapeutic potential for osteoporosis patients with iron overload. However, the direct effects of hepcidin on bone metabolism are still unknown. The mouse genome contains two highly similar hepcidin genes, Hamp 1 and Hamp2, but only Hamp 1 is involved with iron homeostasis in the mouse [8]. It has been shown that hepcidin can regulate cellular iron metabolism through its molecular target ferroportin 1 (FPN1), which is the only known iron exporter in mammals [9, 10]. After hepcidin binds to FPN1, the latter is internalized and degraded, leading to a decreased export of cellular iron [11]. In this way, hepcidin can significantly increase intracellular iron concentrations. The effects of hepcidin have been observed in many types of cells, including enterocytes, macrophages, hepatocytes, placental cells, cardiomyocytes, and osteoblasts [12–16]. However, the effects of hepcidin on intracellular iron in osteoclasts remain unclear now. Bone metabolism in the body involves osteoblastic bone formation as well as osteoclastic bone resorption.
INTRODUCTION Hepcidin is an endogenous peptide hormone involved in the regulation of iron homeostasis in human body. A variety of human diseases are associated with abnormalities in iron metabolism. Hepcidin has been reported to treat diseases characterized by iron overload with depressed levels
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