Adipose–Joint Crosstalk in Obesity–Induced Osteoarthritis: Mechanisms, Biomarkers, and Translational Therapeutic Opportunities

Abstract

Abstract Purpose of Review Obesity-induced osteoarthritis (OA) is emerging as a distinct metabolic phenotype fundamentally different from mechanically driven OA. Current therapies largely target downstream joint damage and fail to address underlying adipose–joint pathological interactions. This review synthesises recent advances in understanding how systemic metabolic dysfunction, adipose tissue inflammation, and cellular heterogeneity revealed by single-cell analyses drive OA pathogenesis, and highlights emerging strategies targeting metabolic dysfunction and chronic inflammation. Recent Findings We critically summarised human and experimental studies investigating the role of dysfunctional adipose depots, including visceral, subcutaneous, and infrapatellar fat, in joint degeneration. Mechanistic findings on adipokine signalling, immune activation, and metabolic stress were integrated with recent single-cell insights and therapeutic interventions addressing systemic metabolism and inflammation. Obesity promotes adipose tissue hypertrophy, hypoxia, and inflammatory adipokine secretion, which remodel systemic metabolism and alter the function of joint-resident cells. Crosstalk between adipocytes, macrophages, fibroblasts, and chondrocytes sustains chronic low-grade inflammation, oxidative stress, and extracellular matrix degradation. Single-cell analyses have revealed fibroblast and macrophage subsets that mediate depot-specific inflammatory circuits. Recent findings also point to metabolic modulators (GLP-1 receptor agonists), anti-adipokine agents, and regenerative strategies as promising interventions to modify disease progression. Summary Obesity-induced OA arises from multi-level metabolic and inflammatory crosstalk between adipose and joint tissues. Deciphering adipose–joint crosstalk provides a foundation for precision therapies that address the upstream metabolic and inflammatory drivers of joint degeneration.