Musculoskeletal traumatic injuries (MTI) involve soft tissue lesions adjacent to a bone fracture leading to fibrous nonunion. The impact of MTI on the inflammatory response to fracture and on the immunomodulation of skeletal stem/progenitor cells (SSPCs) remains unknown. Here, we used single-nucleus transcriptomic analyses to describe the immune cell dynamics after bone fracture and identified distinct macrophage subsets with successive pro-inflammatory, pro-repair and anti-inflammatory profiles. Concurrently, SSPCs transition via a pro- and anti-inflammatory fibrogenic phase of differentiation prior to osteochondrogenic differentiation. In a preclinical MTI mouse model, the injury response of immune cells and SSPCs is disrupted leading to a prolonged pro-inflammatory phase and delayed resolution of inflammation. Macrophage depletion improves bone regeneration in MTI demonstrating macrophage involvement in fibrous nonunion. Finally, pharmacological inhibition of macrophages using the CSF1R inhibitor Pexidartinib ameliorates healing. These findings reveal the coordinated immune response of macrophages and skeletal stem/progenitor cells as a driver of bone healing and as a primary target for the treatment of trauma-associated fibrosis.

肌肉骨骼创伤性损伤 （MTI） 涉及与骨折相邻的软组织病变，导致纤维不连。MTI 对骨折炎症反应和骨骼干/祖细胞 （SSPC） 免疫调节的影响仍然未知。在这里，我们使用单核转录组学分析来描述骨折后的免疫细胞动力学，并确定了具有连续促炎、促修复和抗炎特征的不同巨噬细胞亚群。同时，SSPCs 在成骨软骨分化之前通过促炎和抗炎纤维化分化阶段过渡。在临床前 MTI 小鼠模型中，免疫细胞和 SSPC 的损伤反应被破坏，导致促炎期延长和炎症消退延迟。巨噬细胞耗竭改善了 MTI 的骨再生，表明巨噬细胞参与纤维不连。最后，使用 CSF1R 抑制剂 Pexidartinib 对巨噬细胞的药理学抑制可改善愈合。这些发现揭示了巨噬细胞和骨骼干/祖细胞的协调免疫反应是骨愈合的驱动因素，也是治疗创伤相关纤维化的主要靶点。