Zfp260 choreographs the early stage osteo-lineage commitment of skeletal stem cells

The initial fine-tuning processes are crucial for successful bone regeneration, as they guide skeletal stem cells through progenitor differentiation toward osteo- or chondrogenic fate. While fate determination processes are well-documented, the mechanisms preceding progenitor commitment remain poorly understood. Here, we identified a transcription factor, Zfp260, as pivotal for stem cell maturation into progenitors and directing osteogenic differentiation. Zfp260 is markedly up-regulated as cells transition from stem to progenitor stages; its dysfunction causes lineage arrest at the progenitor stage, impairing bone repair. Zfp260 is required for maintaining chromatin accessibility and regulates Runx2 expression by forming super-enhancer complexes. Furthermore, the PKCα kinase phosphorylates Zfp260 at residues Y173, S182, and S197, which are essential for its functional activity. Mutations at these residues significantly impair its functionality. These findings position Zfp260 as a vital factor bridging stem cell activation with progenitor cell fate determination, unveiling a element fundamental to successful bone regeneration.