Hepcidin-induced reduction in iron content and PGC-1β expression negatively regulates osteoclast differentiation to play a protective role in postmenopausal osteoporosis

Abstract

As a necessary trace element, iron is involved in many physiological processes. Clinical and basic studies have found that disturbances in iron metabolism, especially iron overload, might lead to bone loss and even be involved in postmenopausal osteoporosis. Hepcidin is a key regulator of iron homeostasis. However, the exact role of hepcidin in bone metabolism and the underlying mechanism remain unknown. In this study, we found that in postmenopausal osteoporosis cohort, the concentration of hepcidin in the serum was significantly reduced and positively correlated with bone mineral density. Ovariectomized (OVX) mice were then used to construct an osteoporosis model. Hepcidin overexpression in these mice significantly improved bone mass and rescued the phenotype of bone loss. Additionally, overexpression of hepcidin in OVX mice greatly reduced the number and differentiation of osteoclasts in vivo and in vitro . This study found that overexpression of hepcidin significantly inhibited ROS production, mitochondrial biogenesis, and PGC-1β expression. These data showed that hepcidin protected osteoporosis by reducing iron levels in bone tissue, and in conjunction with PGC-1β, reduced ROS production and the number of mitochondria, thus inhibiting osteoclast differentiation and bone absorption. Hepcidin could provide new targets for the clinical treatment of postmenopausal osteoporosis.

Research Progress of Ferroptosis Regulatory Network and Bone Remodeling in Osteoporosis

“…So far, FPN is the only iron output protein in vertebrates. If the activation of HEP-induced FPN is insufficient or ineffective, iron overload or iron deposition in bones may occur in the body, producing lots of ROS, and ultimately leading to osteoporosis ( 27 ). Jiang et al observed bone loss, bone microstructure damage, bone mineralized area reduction with various density of ferric ammonium citrate (FAC) in OB of zebrafish embryos ( 28 ).…”

LncRNA metastasis‐associated lung adenocarcinoma transcript‐1 promotes osteogenic differentiation of bone marrow stem cells and inhibits osteoclastic differentiation of Mø in osteoporosis via the miR‐124‐3p/IGF2BP1/Wnt/β‐catenin axis

“…The pathogenesis of osteoporosis may be related to the poor regulation of reproductive hormones, calcitonin, growth factors, and various cytokines affecting bone remodeling (Asafo-Adjei et al, 2016). The existing therapeutic methods for osteoporosis mainly include antiresorptive agents and anabolic medications: the previous studies have documented that bisphosphonates and denosumab are the most commonly used antiresorptive therapies (Johnson et al, 2021;Kocjan et al, 2021;Langdahl, 2020); Zhang et al found that hepcidin could protect against osteoporosis by reducing iron level in bone tissues and, in combination with PGC-1β, reduce ROS production and mitochondria, thereby inhibiting osteoclast differentiation and bone resorption (Zhang et al, 2021); additionally, teriparatide and abaloparatide could increase bone mineral density and reduce the risk of fractures (Bernhardsson & Aspenberg, 2018); zoledronic acid and Guilu Erxian Glue could also treat postmenopausal osteoporosis (Si et al, 2020;Xu et al, 2018); despite the certain curative effects, these agents also cause some severe side effects such as inhibition of bone remodeling and increasing the risks of bone necrosis (Asafo-Adjei et al, 2016;Yang et al, 2020). Hence, it could be fruitful to further elucidate the molecular mechanism of osteoporosis and explore novel therapeutic targets.…”

Changes in Metabolism and Mitochondrial Bioenergetics during Polyethylene-Induced Osteoclastogenesis

“…A previous study has shown that the gene expression of PGC-1β in wild-type murine BMMs was higher in RANKL-induced osteoclastogenesis [ 82 ]. Following the over-expression of iron-reducing hormone (Hepcidin), which led to suppression in osteoclast differentiation and bone resorption in BMM isolated from ovariectomized mice, it was found that the level of PGC-1β was low, accompanied with reduced levels of ROS and a lower number of mitochondria in cells [ 83 ]. A reduction in the level of PGC-1β and mitochondrial biogenesis were also observed during the suppression of RANKL-induced osteoclastogenesis and bone resorption following treatment with Cinchonine (CN), an antimalarial drug [ 84 ].…”