The role, mechanisms and therapy potential of synovial macrophages in osteoarthritis

The core mechanism of osteoarthritis involves a chronic inflammatory microenvironment, primarily characterized by synovitis. Within this context, the phenotypic polarization of synovial macrophages plays a pivotal role in maintaining joint homeostasis and driving pathological progression. Under physiological conditions, synovial macrophages in the synovial lining form a barrier and secrete protective substances. Under pathological conditions, they become abnormally polarized and their infiltrations increase, releasing large amounts of inflammatory factors and reactive oxygen species, which disrupt the microenvironment and accelerate cartilage degeneration and pain. While the classical paradigm categorizes macrophage polarization into pro-inflammatory M1 and anti-inflammatory M2 subtypes, emerging studies identify three novel polarization phenotypes of synovial macrophages: Mox (metabolic phenotype), M4 (fibrosis-driving phenotype), and Mreg (regulatory phenotype), which exhibit disease-specific distributions. Targeted regulation of the number or polarization of synovial macrophages provides new therapeutic potentials to alleviate pain and hinder disease progression in osteoarthritis. This review systematically elucidates recent advances in the research on the polarization of synovial macrophages and their roles in osteoarthritis pathogenesis, and analyzes current strategies and therapeutic potentials for the modulation of macrophage behavior, and the issues yet to be explored in this field as well, providing insights for precise osteoarthritis therapy.