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Muscle-to-Bone CX3CL1 Signaling Promotes Skeletal Repair Through CX3CR1+ Osteoprogenitors.
Biorxiv : the Preprint Server for Biology
|June 5, 2026
Summary
Muscle-derived CX3CL1 (chemokine C-X3-C motif ligand 1) signals through its receptor CX3CR1 on osteoprogenitors to enhance bone repair. This pathway is crucial for effective bone regeneration following injury.
Area of Science:
- Biomedical Science
- Regenerative Medicine
- Skeletal Biology
Background:
- Impaired bone repair is linked to muscle loss, suggesting muscle-derived signals are vital for bone regeneration.
- The precise mechanisms of muscle-bone communication in the injury niche remain largely unknown.
Purpose of the Study:
- To elucidate the role of muscle-derived signals in bone repair.
- To identify specific molecular pathways involved in muscle-bone crosstalk during femoral bone healing.
Main Methods:
- Investigated CX3CL1 expression in endothelial cells of muscles near a femoral bone injury site.
- Utilized gene deletion (Cx3cl1 knockout) and lineage tracing to track osteoprogenitor cells.
- Assessed osteoblastogenesis in response to CX3CL1 and evaluated bone repair in aged mice with local CX3CL1 delivery.
Main Results:
- CX3CL1 expression was induced in muscle endothelial cells post-femoral injury.
- Deletion of Cx3cl1 significantly impaired bone healing.
- CX3CR1 was found on PDGFRα⁺ stromal progenitors, which are key osteoprogenitors.
- CX3CL1 stimulation enhanced osteoblastogenesis of these progenitors.
- Local CX3CL1 delivery improved bone repair in older mice by increasing osteoprogenitor accumulation.
Conclusions:
- CX3CL1 is a critical muscle-derived signal that promotes bone repair.
- The pathway involves endothelial CX3CL1 interacting with CX3CR1 on osteoprogenitors.
- This muscle-bone signaling axis represents a potential therapeutic target for enhancing bone regeneration.
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