Immune dysregulation in osteoarthritis: Mechanisms, biomarkers, and therapeutic opportunities

Abstract

Osteoarthritis (OA) is increasingly recognized as a heterogeneous, immune-modulated joint disease in which chronic low-grade synovial inflammation contributes to structural degeneration and pain, challenging its historical classification as a purely mechanical disorder. Central to this paradigm shift is the recognition that synovial immune activation, particularly macrophage-driven inflammatory programs, is a key axis linking tissue damage to nociception and interacting with complementary inflammatory networks that collectively shape disease progression. However, translating these mechanistic insights into effective disease-modifying therapies has remained limited, with biologics targeting individual inflammatory mediators yielding inconsistent clinical benefit, thereby exposing a fundamental disconnect between molecular stratification and therapeutic response. This disconnect reflects the pronounced biological heterogeneity of OA, in which inflammatory activity is neither uniform nor temporally stable across disease stages. Emerging evidence supports the existence of distinct immunopathological endotypes, yet current therapeutic strategies remain largely unstratified and fail to account for this variability. Parallel advances in synovial biology and systems-level profiling have expanded the conceptual framework beyond single-cell pathways to encompass integrated immune-stromal interactions, but these insights have not yet translated into robust clinical decision-support tools. Therapeutically, multiple immune-modulatory approaches, including macrophage reprogramming, broader pathway modulation, and cellular or senescence-targeting strategies, have shown preclinical promise but remain constrained by limited clinical validation and inadequate patient selection frameworks. Across these approaches, a consistent barrier is the lack of reliable, reproducible biomarkers that link immunological heterogeneity to clinically actionable stratification. This review synthesizes current understanding of immune-driven mechanisms in OA, evaluates the translational performance of immunomodulatory interventions, and critically examines the limitations of existing biomarker strategies. It highlights the need for an integrated framework that links synovial immunobiology to endotype-specific patient classification, arguing that biomarker-guided stratification is a prerequisite for achieving precision immunomodulation and meaningful disease modification in OA.