Department of Spine Surgery, People's Hospital of Longhua, Affiliated Hospital of Southern Medical University, Shenzhen, China; Guangzhou University of Chinese Medicine, Guangzhou, China.
Department of Spine Surgery, People's Hospital of Longhua, Affiliated Hospital of Southern Medical University, Shenzhen, China.
Chem Biol Interact. 2024 Aug 25;399:111135. doi: 10.1016/j.cbi.2024.111135. Epub 2024 Jul 4.
Iron overload is a risk factor for osteoporosis due to its oxidative toxicity. Previous studies have demonstrated that an excessive amount of iron increases osteocyte apoptosis and receptor activator of nuclear factor κ-B ligand (RANKL) production, which stimulates osteoclast differentiation in vitro. However, the effects of exogenous iron supplementation-induced iron overload on osteocytes in vivo and its role in iron overload-induced bone loss are unknown. This work aimed to develop an iron overloaded murine model of C57BL/6 mice by intraperitoneal administration of iron dextran for two months. The iron levels in various organs, bone, and serum, as well as the microstructure and strength of bone, apoptosis of osteocytes, oxidative stress in bone tissue, and bone formation and resorption, were assessed. The results showed that 2 months of exogenous iron supplementation significantly increased iron levels in the liver, spleen, kidney, bone tissue, and serum. Iron overload negatively affected bone microstructure and strength. Osteocyte apoptosis and empty lacunae rate were elevated by exogenous iron. Iron overload upregulated RANKL expression but had no significant impact on osteoprotegerin (OPG) and sclerostin levels. Static and dynamic histologic analyses and serum biochemical assay showed that iron overload increased bone resorption without significantly affecting bone formation. Exogenous iron promoted oxidative stress in osteocytes in vivo and in vitro. Additional supplementation of iron chelator (deferoxamine) or N-acetyl-l-cysteine (NAC) partially alleviated bone loss, osteocyte apoptosis, osteoclast formation, and oxidative stress due to iron overload. These findings, in line with prior in vitro studies, suggest that exogenous iron supplementation induces osteoclastogenesis and osteoporosis by promoting osteocyte apoptosis and RANKL production via oxidative stress.
铁过载是骨质疏松症的一个风险因素，因为它具有氧化毒性。先前的研究表明，过量的铁会增加破骨细胞凋亡和核因子κ-B 配体（RANKL）的产生，从而刺激体外破骨细胞分化。然而，外源性铁补充诱导的铁过载对体内破骨细胞的影响及其在铁过载诱导的骨丢失中的作用尚不清楚。本研究旨在通过腹腔内给予铁葡聚糖两个月来建立 C57BL/6 小鼠的铁过载模型。评估了各器官、骨骼和血清中的铁水平，以及骨骼的微观结构和强度、破骨细胞凋亡、骨组织中的氧化应激、骨形成和骨吸收。结果表明，外源性铁补充 2 个月显著增加了肝脏、脾脏、肾脏、骨骼组织和血清中的铁水平。铁过载对骨骼微观结构和强度产生负面影响。外源性铁增加了破骨细胞凋亡和空骨陷窝率。铁过载上调了 RANKL 的表达，但对骨保护素（OPG）和硬化素水平没有显著影响。静态和动态组织学分析和血清生化测定表明，铁过载增加了骨吸收，但对骨形成没有显著影响。外源性铁在体内和体外促进了破骨细胞的氧化应激。铁螯合剂（去铁胺）或 N-乙酰-L-半胱氨酸（NAC）的额外补充部分缓解了铁过载引起的骨丢失、破骨细胞形成和氧化应激。这些发现与先前的体外研究一致，表明外源性铁补充通过促进破骨细胞凋亡和 RANKL 的产生，通过氧化应激诱导破骨细胞生成和骨质疏松症。
