Immune cell senescence and chronic bone diseases: osteoimmune mechanisms and therapeutic perspectives.

Abstract

Immune cell senescence is an important intermediary linking organismal ageing, chronic low-grade inflammation, and disordered bone metabolism. With advancing age, immune cells undergo systemic functional remodeling and exhibit a series of characteristic alterations, including reduced proliferative capacity, skewed differentiation, abnormal migration and homing, impaired phagocytic and clearance functions, and changes in their secretory profile. These changes persistently disrupt the osteoimmune microenvironment and ultimately promote enhanced bone resorption, suppressed bone formation, and deterioration of bone quality. This Review centers on the immunological basis of bone homeostasis and systematically summarizes the major biological features of immune cell senescence, with a particular focus on the key cellular mechanisms through which it drives chronic bone disease. It further analyses its pathological manifestations and disease-specific differences in osteoporosis, osteoarthritis, rheumatoid arthritis, and diabetes-related bone disease. Current evidence indicates that the contribution of immune cell senescence varies across different diseases: its pathogenic association appears to be relatively more direct in osteoporosis and rheumatoid arthritis, whereas in osteoarthritis and diabetes-related bone disease it more often acts as a contributor to inflammatory amplification and microenvironmental deterioration. At present, intervention strategies targeting immune cell senescence mainly focus on modulation of macrophage polarization, immune-mediated clearance of senescent cells, restoration of adaptive immune homeostasis, and MSC-related improvement of the local microenvironment, but overall these approaches remain at the preclinical or early translational stage. Future studies should integrate single-cell sequencing, spatial transcriptomics, and multi-omics approaches to define local immune cell senescence landscapes and establish robust biomarker systems, thereby promoting the transition from mechanistic research to precision intervention in chronic bone diseases.