Osteosarcoma (OS) mortality stems from lung metastases. Matrix metalloproteinases (MMPs) facilitate metastatic dissemination by degrading extracellular matrix components. Herein we studied the impact of targeted MMP downregulation on OS metastasis. Differential gene expression analysis of human OS cell lines revealed high MMP9 expression in the majority of OS cell lines. Furthermore, 143B, a metastatic OS cell line, exhibited increased MMP1 and MMP9 mRNA levels. Gene set enrichment analysis on metastatic and non-metastatic OS patient specimens indicated epithelial-mesenchymal transition as the most enriched gene set, with MMP9 displaying strong association to genes in this network. Using the same dataset, Kaplan-Meier analysis revealed a correlation between MMP1 expression and dismal patient survival. Hence, we undertook targeted suppression of MMP1 and MMP9 gene expression in OS cell lines. The ability of OS cells to migrate and form colonies was markedly reduced upon MMP1 and MMP9 downregulation, whereas their cell proliferation capacity remained intact. MMP9 downregulation decreased tumor growth and lung metastases area in an orthotopic mouse OS model. Consistently, human OS lung metastasis specimens displayed marked MMP9 protein expression. Our findings highlight the role of MMP1 and MMP9 in OS metastasis, warranting further exploration of simultaneous inhibition of MMPs for future OS therapeutics.

中文翻译：

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通过靶向下调MMP1和MMP9抑制骨肉瘤体内转移


骨肉瘤（OS）死亡率源于肺转移。基质金属蛋白酶（MMP）通过降解细胞外基质成分促进转移扩散。在此，我们研究了靶向 MMP 下调对 OS 转移的影响。人类 OS 细胞系的差异基因表达分析揭示了大多数 OS 细胞系中 MMP9 的高表达。此外，143B（一种转移性 OS 细胞系）表现出 MMP1 和 MMP9 mRNA 水平增加。对转移性和非转移性 OS 患者标本的基因集富集分析表明上皮-间质转化是最富集的基因集，MMP9 显示与该网络中的基因有很强的关联性。使用相同的数据集，Kaplan-Meier 分析揭示了 MMP1 表达与患者生存率低之间的相关性。因此，我们对 OS 细胞系中的 MMP1 和 MMP9 基因表达进行了靶向抑制。 MMP1和MMP9下调后，OS细胞迁移和形成集落的能力显着降低，但其细胞增殖能力保持不变。在原位小鼠 OS 模型中，MMP9 下调可减少肿瘤生长和肺转移面积。一致的是，人 OS 肺转移标本显示出显着的 MMP9 蛋白表达。我们的研究结果强调了 MM​​P1 和 MMP9 在 OS 转移中的作用，值得进一步探索同时抑制 MMP 以用于未来的 OS 治疗。