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-1 (IL-1, 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 M) compared with IL-1 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 M vs 1055.0 74.4 ng in IL-1 group).Liraglutide increased ACAN expression at lower concentrations (1.297 0.820 vs 0.260 0.323-fold in IL-1 group), whereas PRG4 expression was higher at day 14 at increased concentrations (0.713 0.07 vs 0.338 0.11-fold in IL-1 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-1 group) and was associated with donor-dependent modulation of ACAN expression (1.09 0.84 vs 0.45 0.13-fold in IL-1 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.