Anti-Inflammatory and Anabolic Effects of Liraglutide on 3D Inflammatory Osteoarthritic Spheroid and Scaffold Models of Human Chondrocytes

OBJECTIVE: Osteoarthritis (OA) is a prevalent age-related joint disease characterized by low-grade inflammation and progressive cartilage degeneration. Liraglutide, a glucagon-like peptide-1 receptor agonist approved for diabetes and obesity, has shown anti-inflammatory and chondroprotective effects in preclinical OA models, but its effects in human 3D chondrocyte systems remain unclear. METHOD: Human articular chondrocytes were cultured as 3D spheroid pellets or seeded into porous polyurethane scaffolds. OA-like inflammation was induced using interleukin-1β (IL-1β, 1 ng/mL), followed by liraglutide treatment. Scaffold constructs were subjected to physiological cyclic mechanical loading (1 h/day for 7 days). Inflammatory mediators, anabolic gene expression, and extracellular matrix features were assessed using biochemical, molecular, and histological analyses. RESULTS: In pellet cultures, liraglutide reduced IL-8 levels (877.8 ± 155.3 ng at 0.5 µM) compared with IL-1β treated controls (3127.0 ± 1140.5 ng) at day 14, with a smaller reduction observed for IL-6 ( 863.6 ± 63.1 ng at 0.5 µM vs 1055.0 ± 74.4 ng in IL-1β group). Liraglutide increased ACAN expression at lower concentrations (1.297 ± 0.820 vs 0.260 ± 0.323-fold in IL-1β group), whereas PRG4 expression was higher at day 14 at increased concentrations (0.713 ± 0.07 vs 0.338 ± 0.11-fold in IL-1β group). In scaffold cultures under mechanical loading, liraglutide reduced IL-8 protein release during early time points (3.782 ± 1.505 vs 10.44 ± 6.524-fold in IL-1β group) and was associated with donor-dependent modulation of ACAN expression (1.09 ± 0.84 vs 0.45 ± 0.13-fold in IL-1β group). Histological analyses indicated preservation of proteoglycan- and type II collagen-rich matrix in liraglutide-treated conditions. CONCLUSION: Physiological mechanical loading is essential for establishing scaffold-based human OA models. Liraglutide modulates inflammatory and matrix-related responses in human 3D chondrocyte systems in a context- and donor-dependent manner, supporting its relevance for translational investigation for OA treatment.