1–2 ​T static magnetic field combined with Ferumoxytol prevent unloading-induced bone loss by regulating iron metabolism in osteoclastogenesis

With the deepening of magnetic biomedical effects and electromagnetic technology, some medical instruments based on static magnetic field (SMF) have been used in orthopedic-related diseases treatment. Studies have shown SMF could combat osteoporosis by regulating the differentiation of mesenchymal stem cells (MSCs), osteoblast and osteoclast. With the development of nanotechnology, iron oxide nanoparticles (IONPs) have been reported to regulate the process of bone anabolism. As for SMF combined with IONPs, studies indicated osteogenic differentiation of MSCs were promoted by the combination of SMF and IONPs. However, there are few reports on the effects of SMF combined with IONPs on osteoclast. Herein, the purpose of this study was to investigate the effects of high static magnetic field (HiSMF) combined with IONPs on unloading-induced bone loss in vivo and osteoclastic formation in vitro, and elucidated the potential molecular mechanisms. In vivo, C57BL/6 ​J male mice were unloaded via tail suspension or housed normally. The hindlimb of mice were fixed and exposed to 1–2 ​T SMF for 1 ​h every day, 10 ​mg/kg of Ferumoxytol or saline were injected by tail vein once a week, last for 4 weeks. Bone microstructure, mechanical properties, and osteoclastogenesis were examined respectively. In vitro, the RAW264.7 ​cells were used to assess the effects of 1–2 ​T SMF combined with IONPs in osteoclastogenesis. The iron content was detected by atomic absorption spectrometry and Prussian blue staining. DCFH-DA and MitoSOX™ fluorescence staining were used to assess oxidative stress levels. NF-κB and MAPK signaling pathways were examined by western blot assay. In vivo, the results showed 1–2 ​T SMF and IONPs prevented the damage to bone microstructure and improved the mechanical properties, diminished the number of osteoclasts in unloaded mice, 1–2 ​T SMF combined with IONPs was found more effective. The iron content in the liver and spleen was reduced by the combination of 1–2 ​T SMF and IONPs, enhancing iron levels in the femur. In vitro, osteoclast formation was inhibited by 1–2 ​T SMF and IONPs treatment, and 1–2 ​T SMF combined with IONPs had a more pronounced effect. Moreover, iron uptake of IONPs in osteoclast was reduced to 1–2 ​T SMF exposure. Oxidative stress levels were decreased in osteoclast differentiation under 1–2 ​T SMF combined with IONPs treatment. Molecularly, the expression of NF-κB and MAPK signaling pathways were inhibited under 1–2 ​T SMF combined with IONPs in osteoclastogenesis. Synthetically, our research illustrated 1–2 ​T SMF combined with IONPs prevented unloading-induced bone loss by regulating iron metabolism in osteoclastogenesis. Translational potential of this article: As a non-invasive alternative therapy, some medical instruments based on SMF have been used for orthopedic-related diseases treatment for their portability, cheapness and safety. Ferumoxytol (Feraheme™), the first FDA-approved IONP drug for the treatment of iron deficiency anemia, has been also adapted in translational research for osteoporosis. Based on the above-mentioned two points, we found the synergistic effects of SMF and Ferumoxytol for treatment of experimental osteoporosis. These results show translational potentials for clinical application.