Research Paper Volume 13, Issue 8 pp 11296—11314
Hepcidin-induced reduction in iron content and PGC-1β expression negatively regulates osteoclast differentiation to play a protective role in postmenopausal osteoporosis
- 1 Department of Orthopaedics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
- 2 Osteoporosis Clinical Center, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
- 3 Institute of Osteoporosis Diagnosis and Treatments of Soochow University, Suzhou 215004, China
- 4 Department of Orthopaedics, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou 215004, China
Received: September 19, 2020 Accepted: November 30, 2020 Published: April 4, 2021https://doi.org/10.18632/aging.202817
How to Cite
Copyright: © 2021 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.
PGC-1β: peroxisome proliferator-activated receptor gamma coactivator-1β; OVX: ovariectomized; TAM: tamoxifen; micro-CT: micro-computed tomography; ROS: reactive oxygen species; RANKL: receptor activator for nuclear factor-κβligand; RANK: receptor activator for nuclear factor-κβ; OPG: osteoprotegerin; ERs: estrogen receptors; BMSCs: bone marrow mesenchymal stem cells; BMP-2: bone morphogenetic protein 2; FAC: ferric ammonium citrate; TNF-α: tumor necrosis factor α; IL-6: interleukin 6; PPARγ: peroxisome proliferator activated receptor gamma γ; FPN1: ferroportin 1; SPF: specific pathogen free; E2: estrogen; β-CTX: β-cross-linked C-telopeptide of type I collagen; PFA: polyformaldehyde; BMD: bone mineral density; BV/TV: percent bone volume; Tb.Th: trabecular thickness; Tb.N: trabecular number; Tb.Sp: trabecular separation; FBS: fetal bovine serum; TRAP: tartrate-resistant acid phosphatase; WGA: Wheat germ agglutinin; DAB: 3,3’-diaminobenzidine; ALP: alkaline phosphatase; RUNX2: runt-related transcription factor 2; BGLAP: bone gamma-carboxyglutamate protein; MMP-9: matrix metalloprotein 9; PTK2β: protein tyrosine kinase 2β; NRF: nuclear respiratory factor; DFO: deferoxamine.