Muscle-to-Bone CX3CL1 Signaling Promotes Skeletal Repair Through CX3CR1+ Osteoprogenitors

In the context of muscle loss, bone repair is impaired, suggesting that muscle derived signals contribute to bone regeneration. However, how muscle surrounding the injury site communicates with the bone repair niche remains unclear. Here we found that CX3CL1 expression was induced in endothelial cells in muscle surrounding a femoral bone injury site. Deletion of Cx3cl1 impaired bone healing, demonstrating a functional role for CX3CL1 in bone repair. A CX3CL1 receptor, CX3CR1, was expressed by PDGFRα⁺ stromal progenitors and lineage tracing showed that CX3CR1 expressing osteoprogenitor lineage cells accumulated at the injury site during repair. PDGFRα⁺ stromal progenitors showed enhanced osteoblastogenesis in response to recombinant CX3CL1. In older mice, local CX3CL1 delivery increased PDGFRα⁺CX3CR1⁺ osteoprogenitor accumulation and improved bone repair. These findings identify a muscle bone signaling pathway in which endothelial CX3CL1 promotes bone repair through CX3CR1 expressing osteoprogenitors.