Pathological mechanisms of long non-coding RNA FOXD2-AS1 promoting osteosarcoma mediated by the COI-1/OCN/Runx-2 signaling pathway

Introduction Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. Despite three decades of research efforts, no significant improvement in patient survival rates has been achieved, highlighting the urgent need for in-depth investigation into its pathogenesis to develop novel therapeutic strategies and more effective drugs. FOXD2-AS1, a long non-coding RNA, has been implicated in the prognosis and survival of various cancers, but its role in OS remains underexplored. This study therefore aimed to investigate the functional involvement of FOXD2-AS1 in OS progression and to evaluate a biocompatible delivery system for its in vitro and in vivo application. Methods We synthesized mPEG-PDPA hydrogel via free radical polymerization of 2-(diisopropylamino)ethyl methacrylate (PDA) and polyethylene glycol monomethyl ether acrylate (mPEG-AC), and employed this hydrogel as a delivery vehicle for FOXD2-AS1. The biocompatibility and safety of the empty hydrogel were first validated through both in vitro cell assays and in vivo animal experiments. To explore the mechanistic actions of FOXD2-AS1, we performed real-time quantitative PCR and Western blot analyses, and conducted transcriptome profiling to identify downstream pathways and associated genes. Results and Discussion Our results demonstrated that the mPEG-PDPA hydrogel itself was non-toxic and reliable as a delivery vehicle. Functionally, FOXD2-AS1 promoted alkaline phosphatase (ALP) release and exacerbated the inflammatory response, thereby accelerating the development and deterioration of OS. Mechanistically, FOXD2-AS1 activated the F-box protein Coronatine Insensitive 1 homolog (COI-1)/OCN/Runx-2 signaling pathway, as confirmed by qPCR and Western blot. Transcriptome analysis further revealed that this process involved changes in cell migration, apoptosis, and cell cycle regulation, with CPS1-IT1, ANKRD10-IT1, TBC1D3P1-DHX40P1, and RGS5 identified as key associated genes. Collectively, our findings provide new insights into the pathological mechanisms of OS and offer valuable data support for future therapeutic strategy development.