Beyond M1/M2: The Pivotal Role of Macrophage Metabolic Reprogramming in Chronic Bone Disease and Targeted...

The progression of chronic bone diseases is intricately linked to dysregulated macrophage polarisation. However, a comprehensive understanding of the complex interplay between macrophage polarisation and metabolic reprogramming in the context of bone disorders remains elusive. Thus, this review conducted a systematic search of major databases, including PubMed, using combinations of keywords such as "macrophage polarisation," "immunometabolism," "metabolic reprogramming," and "chronic bone diseases" (including "osteoporosis," "osteoarthritis," and "periodontitis"). Inclusion criteria prioritised original research published within the last five years to capture recent advances. Diverging from previous reviews constrained by the classical M1/M2 dichotomy, this article aims to delineate the heterogeneity and functional plasticity of macrophages within the bone microenvironment, emphasising metabolic reprogramming as a central mechanism driving the dynamic behaviour of macrophages across various skeletal pathologies. Furthermore, this review highlights the pivotal roles of specific metabolites-such as succinate, itaconate, and citrate-within the osseous microenvironment, underscoring their influence on macrophage phenotypic transitions and the regulation of bone metabolic homeostasis. Finally, this article envisages innovative therapeutic strategies targeting the "metabolism-immunity axis," encompassing the design of nano-delivery systems to modulate macrophage metabolism, the utilisation of engineered extracellular vesicles, the development of immunometabolism-modulating biomaterials, and the exploration of naturally occurring bioactive molecules. Based on these findings, the present work proposes the "metabolism-immunity-skeleton" axis as a theoretical framework, thereby establishing a robust foundation for the development of precision metabolic immunotherapy tailored to a spectrum of chronic bone diseases.