FGF-23 regulates MMP-14 expression and angiogenesis via the p85/Akt/mTOR signaling pathway in osteosarcoma.

Osteosarcoma is a highly aggressive bone malignancy in which angiogenesis plays a crucial role in tumor progression. However, the molecular mechanisms underlying osteosarcoma-associated angiogenesis remain incompletely understood. In this study, we investigated the role of fibroblast growth factor-23 (FGF-23) in regulating angiogenesis in osteosarcoma. Bioinformatics analysis of the GSE218035 dataset revealed that matrix metalloproteinases (MMPs), particularly MMP-14, are significantly upregulated in osteosarcoma tissues. Functional assays demonstrated that FGF-23 induces MMP-14 expression in osteosarcoma cells and enhances endothelial tube formation, whereas silencing MMP-14 abolishes these effects. Mechanistic studies further showed that FGF-23 activates the p85/Akt/mTOR signaling pathway, leading to increased MMP-14 expression and angiogenic activity. Inhibition of pathway components by pharmacological inhibitors or siRNA significantly attenuated FGF-23-induced responses. In vivo, FGF-23 overexpression promoted tumor growth and vascularization, accompanied by elevated expression of MMP-14 and the endothelial marker CD31. Collectively, these findings demonstrate that FGF-23 promotes osteosarcoma angiogenesis through regulation of MMP-14 via the p85/Akt/mTOR signaling pathway and suggest that targeting this axis may provide a potential therapeutic strategy.