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.