Glucagon-like peptide 2 (GLP2) is a proglucagon-derived peptide that is involved in the regulation of energy absorption and exerts beneficial effects on glucose metabolism. However, the exact mechanisms underlying the GLP2 during osteogenic differentiation has not been illustrated. Herein, we indicated that GLP2 was demonstrated to result in positive action during the osteogenic differentiation of human osteosarcoma cells. Our findings demonstrate that GLP2 inhibis the growth of osteosarcoma cells in vivo and in vitro. Mechanistic investigations reveal GLP2 inhibits the expression and activity of nuclear factor κB (NF-κB), triggering the decrease of c-Myc, PKM2, and CyclinD1 in osteosarcoma cells. In particular, rescued NF-κB abrogates the functions of GLP2 in osteosarcoma cells. Strikingly, GLP2 overexpression significantly increased the expression of osteogenesis-associated genes (e.g., Ocn and PICP) dependent on c-Fos-BMP signaling, which promotes directed differentiation from osteosarcoma cells to osteoblasts with higher alkaline phosphatase activity. Taken together, our results suggested that GLP2 could be a valuable drug to promote directed differentiation from osteosarcoma cells to osteoblasts, which may provide potential therapeutic targets for the treatment of osteosarcoma.

胰高血糖素样肽 2 (GLP2) 是一种胰高血糖素原衍生肽，参与能量吸收的调节并对葡萄糖代谢发挥有益作用。然而，尚未阐明成骨分化过程中 GLP2 的确切机制。在此，我们指出 GLP2 被证明在人骨肉瘤细胞的成骨分化过程中产生积极作用。我们的研究结果表明 GLP2在体内和体外抑制骨肉瘤细胞的生长. 机制研究表明 GLP2 抑制核因子 κB (NF-κB) 的表达和活性，引发骨肉瘤细胞中 c-Myc、PKM2 和 CyclinD1 的减少。特别是，获救的 NF-κB 会破坏 GLP2 在骨肉瘤细胞中的功能。引人注目的是，GLP2 过表达显着增加了依赖于 c-Fos-BMP 信号的成骨相关基因（例如，Ocn 和 PICP）的表达，这促进了骨肉瘤细胞向具有更高碱性磷酸酶活性的成骨细胞的定向分化。综上所述，我们的结果表明 GLP2 可能是一种有价值的药物，可以促进骨肉瘤细胞向成骨细胞的定向分化，这可能为骨肉瘤的治疗提供潜在的治疗靶点。