Prediction and validation based on scRNA-seq: ETS2 targets CEBPB to mediate osteoclast differentiation in osteoarthritis progression.

Abstract

This study aims to identify key molecular targets driving osteoclast (OC)-mediated osteoarthritis (OA) progression and to explore the underlying mechanisms. Analysis of OA-related scRNA-seq data revealed that the transcription factor (TFs) ETS2 is identified as a hub gene promoting OC differentiation in OA progression. In Silico Perturbation and in vitro perturbation experiments demonstrated that knockdown of ETS2 inhibits OC differentiation. Transcriptional regulatory network analysis and combined Cut&Tag with ATAC-seq analysis indicated that ETS2 regulates OC differentiation by targeting and enhancing the expression of CEBPB. This conclusion was validated by in vitro rescue experiments. In vivo experiments showed that knockdown of ETS2 decreases the number of OCs in the subchondral bone of DMM model mice and inhibits subchondral bone remodeling and OA progression. In summary, our findings indicate that ETS2 regulates OC differentiation by targeting and modulating the expression of CEBPB. Knockdown of ETS2 can alleviate subchondral bone remodeling and OA progression in DMM model mice, providing new insights into the pathogenesis and treatment of OA.