The CX3CL1-CX3CR1 axis in mesenchymal stem cell regulation and bone diseases

The chemokine axis CX3CL1-CX3CR1 is involved in the whole process of bone remodeling, bone injury repair, and inflammation-mediated bone destruction, making it both a diagnostic marker and a potential target for therapy. This article focuses on bone marrow mesenchymal stem cells (BMSCs) to explain the bidirectional mechanism of CX3CL1-CX3CR1 in regulating bone homeostasis, compares three types of targeting strategies, and proposes a local delivery approach. The regulatory effect of CX3CL1 is concentration-dependent: transient or moderate sCX3CL1 signaling is associated with a pro-repair macrophage phenotype, while persistent pathological elevation promotes M1 polarization and bone resorption; however, direct evidence for the low intramedullary concentration of the M2 axis is limited. This article focuses on analyzing the hormone regulatory pathways of three endocrine-related bone diseases (postmenopausal osteoporosis, diabetic bone disease, and hyperthyroidism-induced bone injury), and compares the advantages and disadvantages of monoclonal antibodies, small molecule drugs, and bone nanocarriers. The CX3CL1-CX3CR1 axis represents a candidate research target for pre-clinical investigations into endocrine-related bone diseases, yet substantial unresolved barriers limit its translational progression. Local targeted delivery strategies may offer conceptual directions for future pre-clinical investigation for solving the treatment challenges brought about by the bidirectional effects of this pathway, but their clinical feasibility still needs to be verified. Notably, critical in-vivo concentration thresholds distinguishing protective versus pathological CX3CL1 effects have not been established, and evidence supporting concentration-dependent M1/M2 macrophage polarization is largely derived from non-bone systems.