Skeletal system diseases, including osteoarthritis (OA), osteoporosis (OP), and spinal cord injury (SCI), represent a growing global health burden, with chronic low-grade inflammation and macrophage polarization imbalance as shared pathological features. Exosomes have emerged as pivotal mediators of intercellular communication in the bone microenvironment. By delivering diverse bioactive cargoes-including microRNAs, long non-coding RNAs, and functional proteins-they can regulate macrophage phenotypes and modulate the balance between pro-inflammatory and anti-inflammatory states. This review systematically integrates current knowledge on exosome-mediated macrophage polarization in skeletal disorders from a cross-disease perspective. We propose that exosome-based modulation of macrophage phenotypes offers a novel immunotherapeutic paradigm for these conditions. We first outline the biogenesis and cargo-sorting mechanisms of exosomes and highlight the distinct immunoregulatory properties of exosomes derived from different cell sources, including mesenchymal stem cell-derived exosomes (MSC-Exos) that preferentially drive M2 polarization, and M1/M2 macrophage-derived exosomes that respectively sustain pro-or anti-inflammatory feedback loops. We then dissect the key signaling pathways-NF-κB, JAK/STAT, PI3K/AKT/mTOR, and MAPK-through which exosomal components orchestrate macrophage M1/M2 transition at transcriptional, post-transcriptional, and metabolic levels. Importantly, we emphasize recent advances in engineering strategies, such as donor cell preconditioning (hypoxia, cytokines, lipopolysaccharide) and cargo loading (electroporation, 3D culture), which overcome the inherent limitations of natural exosomes and enable precise control of macrophage polarization. By synthesizing evidence from OA, OP, SCI, and other bone-related diseases, we reveal that exosome-based restoration of M1/M2 balance may represent a promising strategy for disease modification. This review not only provides a comprehensive theoretical reference but also highlights forward-looking avenues for precision immunotherapy in musculoskeletal diseases, thereby bridging the gap between basic research and clinical translation.
Lei Huang, Yu Huang, Changlin Zhou et al.· International Immunopharmaco...· 1 citation
Osteoarthritis (OA) is a chronic degenerative joint disease characterized predominantly by articular cartilage degeneration, synovial inflammation, subchondral bone remodeling, and progressive impairment of joint function. Its pathogenesis is multifactorial and involves several interrelated pathological processes, including chronic low-grade inflammation, oxidative stress, dysregulated extracellular matrix metabolism, chondrocyte senescence and apoptosis, and microcirculatory dysfunction. At present, OA management remains largely focused on symptomatic relief, and disease-modifying agents capable of effectively delaying or reversing structural disease progression remain unavailable. As established HMG-CoA reductase inhibitors, statins exert a range of pleiotropic biological effects beyond lipid lowering, including anti-inflammatory and antioxidant actions, immunomodulatory activity, enhancement of endothelial function, and regulation of bone metabolism. These effects are closely aligned with the central pathogenic mechanisms implicated in OA. However, whether statins exert disease-modifying effects in OA, as well as the mechanisms underlying such effects, has not been systematically elucidated. In addition, current evidence is derived predominantly from in vitro experiments and animal models, whereas clinical evidence remains limited and heterogeneous. This review aims to evaluate the potential disease-modifying effects of statins in OA. Specifically, it systematically summarizes their mechanisms of action in the synovium, cartilage, subchondral bone, and vascular-metabolic microenvironment, reviews evidence from basic and clinical studies, and discusses the principal limitations and knowledge gaps in the current literature. Available studies indicate that statins may confer protective effects on OA-related tissues by modulating key pathological processes, including inflammation, oxidative stress, extracellular matrix metabolism, and bone remodeling. Nevertheless, robust high-quality clinical evidence supporting the use of statins as a disease-modifying therapeutic strategy for OA is still lacking. Future well-designed randomized controlled trials, integrated with disease phenotyping and biomarker-based investigations, are warranted to further define the clinical relevance, optimal target populations, and therapeutic value of different statin types, doses, and routes of administration.
Haitao Dong, Xianxu Zhang, Yannian Luo et al.· International Immunopharmaco...· 0 citations
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