Chen Xin, Wang Jianping, Zhen Chenxiao, Zhang Gejing, Yang Zhouqi, Xu Youjia, Shang Peng
School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China.
Research & Development Institute in Shenzhen, Northwestern Polytechnical University, Shenzhen, 518057, China.
BMC Musculoskelet Disord. 2025 Mar 18;26(1):276. doi: 10.1186/s12891-025-08515-0.
An oligopeptide hepcidin is encoded by the human HAMP gene (Hamp in mice). Its deficiency can result in iron overload, while excess may lead to iron deficiency. Hepcidin knockout mice exhibited iron accumulation in multiple tissues, accompanied by degeneration of bone microarchitecture and reduced biomechanical properties. Astronauts who are exposed to weightlessness during prolonged spaceflight experience bone loss. After space missions, an interrelation exists between iron stores and bone mineral density (BMD). Bone loss in mice due to unloading is linked to iron excess and involves hepcidin. The potential role of hepcidin in unloading-induced bone loss remains unclear.
Our study conducted relevant experiments using hepcidin knockout mice and their primary osteoblasts as the research subjects. We used the hindlimb unloading (HLU) model and the random positioning machine (RPM) system to simulate weightlessness in vivo and in vitro.
HLU mice exhibited reduced hepcidin levels in the serum and liver. Hepcidin knockout further diminished BMD and bone mineral content (BMC) in the femurs of HLU mice. Similarly, the bone volume fraction (BV/TV) and connectivity density (Conn.Dn) followed this downward trend, whereas trabecular separation (Tb.Sp) showed an inverse pattern. Moreover, hepcidin knockout decreased the ultimate load and elastic modulus in the tibias of HLU mice. Hepcidin knockout decreased PINP levels in the serum, a commonly used marker for bone formation, alongside elevated iron levels in the serum, liver, and bone of HLU mice. We also found higher serum MDA and SOD levels in these mice. In vitro, experimental data indicated that hepcidin knockout suppresses the osteoblastic differentiation capacity under RPM conditions. Additionally, this condition upregulates SOST protein levels and downregulates LRP6 and β-catenin protein levels in osteoblasts.
Hepcidin knockout exacerbates bone loss in HLU mice, most likely due to reduced osteoblastic activity.
人HAMP基因（小鼠中为Hamp）编码一种寡肽铁调素。其缺乏会导致铁过载，而过量则可能导致缺铁。铁调素基因敲除小鼠在多个组织中表现出铁蓄积，同时伴有骨微结构退变和生物力学性能降低。长时间太空飞行中暴露于失重环境的宇航员会出现骨质流失。太空任务结束后，铁储备与骨矿物质密度（BMD）之间存在相互关系。小鼠因失重导致的骨质流失与铁过量有关，且涉及铁调素。铁调素在失重诱导的骨质流失中的潜在作用仍不清楚。
我们的研究以铁调素基因敲除小鼠及其原代成骨细胞为研究对象进行了相关实验。我们使用后肢卸载（HLU）模型和随机定位机（RPM）系统在体内和体外模拟失重。
HLU小鼠血清和肝脏中的铁调素水平降低。铁调素基因敲除进一步降低了HLU小鼠股骨的骨密度和骨矿物质含量（BMC）。同样，骨体积分数（BV/TV）和连通性密度（Conn.Dn）也呈下降趋势，而小梁间距（Tb.Sp）则呈相反模式。此外，铁调素基因敲除降低了HLU小鼠胫骨的极限负荷和弹性模量。铁调素基因敲除降低了血清中PINP水平，PINP是常用的骨形成标志物，同时HLU小鼠血清、肝脏和骨骼中的铁水平升高。我们还发现这些小鼠血清中的丙二醛（MDA）和超氧化物歧化酶（SOD）水平较高。在体外，实验数据表明，铁调素基因敲除在RPM条件下抑制成骨细胞分化能力。此外，这种情况上调了成骨细胞中sost蛋白水平，下调了LRP6和β-连环蛋白蛋白水平。
铁调素基因敲除加剧了HLU小鼠的骨质流失，最可能的原因是成骨细胞活性降低。
