Macrophage polarization: A bridge connecting osteoarthritis and osteoporosis

Macrophage polarization plays a pivotal role in maintaining bone homeostasis and serves as a crucial mechanistic bridge in the comorbidity of osteoarthritis (OA) and osteoporosis (OP). Macrophages exhibit functional plasticity, polarizing into pro-inflammatory M1 and anti-inflammatory M2 phenotypes in response to various environmental cues. Recent advances in macrophage biology have highlighted the significant heterogeneity of macrophages, which display a spectrum of phenotypic states beyond the classical M1/M2 dichotomy. Dysregulated macrophage polarization, particularly an excess of M1 macrophages, is central to the pathophysiological mechanisms underlying OA and OP. This review systematically explores how altered macrophage polarization influences OA and OP pathogenesis, emphasizing its role in inflammatory responses, metabolic syndrome, and the mechanical microenvironment. In particular, macrophage polarization within the subchondral bone-cartilage interface has emerged as a key factor in exacerbating joint and bone degeneration. Imbalances in macrophage polarization are shown to contribute to cartilage degradation, bone loss, and disrupted bone remodeling processes in these diseases. Additionally, exosomal non-coding RNAs (Exos-ncRNAs) have been identified as important modulators of macrophage polarization, offering potential therapeutic targets for restoring M2-mediated repair functions and reducing M1-driven inflammation. Targeting specific macrophage polarization pathways holds promise for developing integrated therapeutic strategies to address both OA and OP by restoring immune-metabolic homeostasis, enhancing tissue repair, and promoting bone regeneration.