Advances in the study of the role of bone immunity in physiological and pathological processes related to bone metabolism.
BACKGROUND Bone metabolism is regulated by immune cells that maintain skeletal homeostasis through cytokine secretion and cell interactions. Disruption of this regulation-by inflammation, autoimmunity, or aging-drives pathological bone diseases including osteoporosis and rheumatoid arthritis. Single-cell technologies and exosome biology have revealed previously unrecognized immune subsets and regulatory layers within the bone microenvironment. MAIN BODY Osteoimmunology has elucidated the interplay between macrophages, T cells, B cells, NK cells, neutrophils, dendritic cells, and mast cells in bone remodeling. These cells form dynamic interaction networks-Treg-M2 feedback loops, Th17-neutrophil amplification, and B-T-osteoclast axes-that collectively determine net skeletal outcome. Immune cells regulate osteoclast and osteoblast function through TNF-α, IL-6, IL-17 A, and RANKL, with highly context-dependent effects. Immunosenescence has emerged as a key driver of age-related bone loss. The RANKL/RANK/OPG axis serves as the central signaling hub, modulated by Sema3A/Wnt/β-catenin, PI3K/Akt, JAK/STAT, and Notch. Dysregulation of these pathways underlies osteoporosis, RA, intervertebral disc degeneration, ankylosing spondylitis, and cancer bone metastasis. Clinically, denosumab and cytokine-targeted biologics (anti-TNF-α, anti-IL-6R, anti-IL-17 A) demonstrate bone-protective effects, while bispecific antibodies, CAR-Treg cells, and senolytics represent emerging strategies. CONCLUSIONS The net skeletal effect of the immune system is determined by the balance of interacting cell types, cytokine networks, and signaling pathways. Future progress requires single-cell spatiotemporal multi-omics, cell-type-specific immunotherapies, elucidation of the gut-bone axis, and systematic evaluation of combination strategies pairing immunomodulators with anti-resorptives, anabolic agents, or senolytics.