CCN1 as a compartment-specific biomarker of active microenvironmental remodeling: evidence from bone repair, aging, inflammation, and cancer.

Cellular communication network factor 1 (CCN1) is a secreted matricellular protein induced by growth factors, mechanical stress, hypoxia, and tissue injury and regulates diverse cellular processes through interactions with integrins, heparan sulfate proteoglycans, and extracellular matrix (ECM) components. Although prior reviews have broadly summarized CCN1 biology, its potential as a biomarker warrants a more focused synthesis of empirical evidence. Here, we propose that CCN1 should be viewed not as a generic disease marker, but as a compartment-specific biomarker of active microenvironmental remodeling. Emerging evidence identifies CCN1 as a central regulator of bone pathology and cancer progression, functioning at the intersection of osteogenesis, osteolysis, angiogenesis, stromal remodeling, immune modulation, and metastatic colonization. Within the skeletal niche, CCN1 is produced by tumor cells, stromal fibroblasts, endothelial cells, and bone-resident cells, where it influences osteoblast and osteoclast activity and promotes vascular niche formation. CCN1 also participates in fracture repair, bone marrow mesenchymal stem cell aging, epithelial-mesenchymal transition, and tumor dissemination, highlighting its roles in both regenerative and pathological processes. Importantly, CCN1 exists in distinct biological compartments, including ECM-bound, soluble circulating, extracellular vesicle-associated, and tumor cell-associated pools. These compartments likely convey different biological information, ranging from local osteogenic to systemic injury, inflammation, and metastatic spread. While circulating CCN1 is measurable and shows promise as a minimally invasive biomarker, its interpretation must account for disease context, timing, and biological compartment. We conclude that CCN1 represents a compelling translational candidate linking bone remodeling and cancer biology, with future studies needed to validate its biomarker utility in skeletal disease and metastasis.