Skeletal Stem Cells Rescue Radiation-Induced Osteogenic Precursor Cell Dysfunction via the Wnt/β-Catenin Signaling Pathway

Objective: Skeletal stem cells (SSCs), a specialized subset of mesenchymal stem cells, drive bone regeneration. This study aimed to characterize the pathological effects of ionizing radiation (IR) on osteogenic precursor cells (MC3T3-E1) and to elucidate the therapeutic efficacy and underlying molecular mechanisms of SSC-mediated rescue. Methods: Experiments were performed using clonogenic assay, micronucleus assay, flow cytometry, osteogenic differentiation assessment, migration assay, and animal model establishment. Results: , IR led to deterioration of the skeletal microarchitecture,as evidenced by reduced bone mineral density (BMD), decreased bone volume fraction (BV/TV), and a concomitant increasee in marrow adiposity and osteoclastogenesis. Notably, SSC treatment significantly reversed these deleterious effects in both cellular and animal models. Mechanistically, SSC intervention upregulated key osteogenic regulators (RUNX22, COL1A1, and OCN) and stabilized β-catenin. Crucially, the radioprotective efficacy of SSCs was abrogated by the Wnt/β-catenin inhibitor MSAB, demonstrating the pathway's indispensable role in the rescue process. Conclusions: This study indicates that SSCs effectively alleviate IR-induced injury to osteoblast progenitor cells, providing compelling evidence and establishing a novel therapeutic paradigm for treating radiation-related skeletal complications.