The function of GPCRs in different bone cells.

G protein-coupled receptors (GPCRs) are recognized as critical therapeutic targets in bone disorders, owing to their multifaceted regulatory roles across diverse bone cell lineages. This review systematically catalogs GPCR expression and functional heterogeneity in key bone cells: 12 GPCRs in mesenchymal stem cells (MSCs) orchestrate lineage specification; 21 GPCRs in osteoblasts/osteocytes mediate matrix mineralization and mechanotransduction; 23 GPCRs in macrophages/osteoclasts regulate inflammatory bone resorption; 31 GPCRs in chondrocytes govern endochondral ossification and osteoarthritis pathogenesis; and 8 GPCRs in other cell types modulate bone-related physiological processes. By integrating canonical signaling axes-cAMP/PKA-dependent transcriptional networks, PLC-β/IP3-driven calcium signaling, and NF-κB-modulated immuno-skeletal interactions-we elucidate how GPCRs dynamically coordinate cellular plasticity to maintain skeletal homeostasis. This work establishes a multidimensional research framework integrating historical context, molecular mechanisms, and cutting-edge methodologies to advance GPCR-targeted therapies for bone-related diseases. Moreover, this review provides insights for clinical translation, including biased agonism and allosteric modulation precision strategies to restore skeletal equilibrium in osteoporosis, arthritis, and regenerative medicine.