Pulsed electromagnetic fields induce ferroptosis in osteosarcoma cells and promote osteogenic differentiation.
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UNLABELLED: Osteosarcoma is the most common malignant bone tumor in children and adolescents, which predominantly arises in the metaphyses of long bones. Characterized by high malignancy and a high tendency toward pulmonary metastasis, it confers a poor patient prognosis. At present, the standard-of-care therapy consists of radical wide resection combined with postoperative adjuvant radiotherapy and chemotherapy. Nevertheless, invasive treatments such as chemotherapy are accompanied by prominent adverse reactions. Accordingly, non-invasive and safe physical therapies have gained growing research interest. As a non-invasive physical therapeutic modality, pulsed electromagnetic fields (PEMF) have exhibited anti-tumor activities against multiple malignancies. However, its therapeutic efficacy, underlying molecular mechanisms, and influences on normal bone tissue in osteosarcoma remain poorly understood. METHODS: In this study, osteosarcoma cell lines and osteoblast cell lines were exposed to pulsed electromagnetic fields in vitro, with untreated cells set as the control group. CCK-8 and Transwell assays were performed to evaluate cell proliferation, migration and cell death. Western blotting and quantitative real-time PCR (qPCR) were used to detect the expression levels of key ferroptosis-related molecules and lipid peroxidation markers. Furthermore, the in-vivo anti-tumor effect of PEMF was verified using a nude-mouse osteosarcoma metastatic tumor model. Cytological and animal behavioral assays were applied to assess bone mineral density, trabecular architecture and osteogenic differentiation markers of normal bone tissue. RESULTS: PEMF markedly suppressed the proliferation and migration of osteosarcoma cells and triggered ferroptosis, manifested by down-regulated expression of GPX4 and SLC7A11 as well as elevated malondialdehyde (MDA) levels. The above-mentioned phenotypes could be partially reversed by the ferroptosis inhibitor deferoxamine (DFO). In vivo experiments demonstrated that PEMF significantly reduced the number of pulmonary metastatic lesions and prolonged the survival time of nude mice. Meanwhile, PEMF facilitated osteoblast differentiation and improved bone mineral density and trabecular-bone-related parameters, without obvious damage observed to normal bone tissue. CLINICAL IMPLICATIONS AND LIMITATIONS: This study indicates that PEMF represents a promising non-invasive adjuvant therapeutic option after osteosarcoma resection. It can inhibit tumor metastasis as well as promote bone repair, and therefore possesses potential for clinical translation. Nonetheless, evaluations regarding long-term safety and effectiveness are still absent. The adopted electromagnetic-field parameters and frequency range are relatively limited. Further multi-parameter optimization and validation in larger-scale animal models are required.