Basonuclin-2 promotes fracture repair through NuRD-dependent chromatin remodeling in periosteal stem cells.

Bone fracture healing remains a significant challenge in orthopedics, as injury-responsive skeletal stem cell (SSC) populations and the regulatory mechanisms governing SSC activation during nonunion fracture repair remain poorly delineated. This study identifies zinc finger transcription factor basonuclin-2 (BNC2) as a skeletal fracture repair control factor in periosteal stem cells. BNC2 marks quiescent periosteal cells during homeostasis and is significantly upregulated upon injury in mice, driving endochondral ossification post-fracture via clonal expansion. Moreover, knockout of Bnc2 in Prx1-cre(+) cells (not Ocn-cre(+) osteoblasts or LepR-creER(+) BMSCs) resulted in impaired fracture healing, suppressing SSC proliferation. Mechanistically, ATAC-seq revealed that BNC2 deletion reduced chromatin accessibility at promoter regions of proliferation genes, hindering transcriptional activation. Additionally, BNC2 regulates histone H3 acetylation by interacting with the NuRD complex. Pharmacologically inhibition of HDAC1/2 activity partially ameliorated the fracture repair defects observed in Prx1-cre; Bnc2(f/f) mice. Collectively, we identified BNC2(+) cells as a rapidly expanding periosteal cell population inducing endochondral ossification niches during repair, providing potential therapeutic strategies for nonunion fractures.