SPARC from Young CSF Rejuvenates aged Skull Bone Marrow by targeting neutrophil-derived MMP25

Skeletal aging remains poorly understood, particularly in craniofacial bones that interface closely with the central nervous system. Here, we identify a unique aging microenvironment in skull bone marrow (BM) characterized by neutrophil accumulation and elevated MMP25, which drives skull skeletal stem cell (SSC) dysfunction via NF-κB-mediated inflammation. Neutrophil-specific deletion of Mmp25 alleviates age-associated bone loss and preserves SSC regenerative capacity. We further demonstrate that cerebrospinal fluid from young mice (yCSF) rejuvenates aged SSCs, with Secreted Protein Acidic and Rich in Cysteine (SPARC) identified as a key youth-associated factor diminished in aged CSF. Mechanistically, SPARC suppresses PU.1-dependent transcription of MMP25, thereby reducing inflammation and restoring osteogenic potential in aged SSCs. These findings define a CSF-skull BM axis linking neuroimmune signaling to skeletal aging and identify the SPARC-PU.1-MMP25 pathway as a therapeutic target for craniofacial bone regeneration.