Liraglutide reduces inflammation and boosts anabolic markers in human osteoarthritic chondrocyte 3D models.

Osteoarthritis (OA) is a debilitating age-related joint disease marked by chronic low-grade inflammation and progressive cartilage degeneration, leading to pain and reduced mobility. Current treatments primarily manage symptoms, failing to halt disease progression or restore cartilage. Liraglutide, a GLP-1R agonist, has shown promise in preclinical OA models with anti-inflammatory and chondroprotective effects. However, its direct impact on human chondrocytes within physiologically relevant 3D models, crucial for understanding its therapeutic potential, remained largely unexplored.

Human articular chondrocytes were cultivated in two 3D models: spheroid pellets and porous polyurethane scaffolds. To mimic OA, inflammation was induced using interleukin-1β (IL-1β, 1 ng/mL). These models were then treated with liraglutide at various concentrations. Scaffold cultures were additionally subjected to physiological cyclic mechanical loading for 1 hour/day over 7 days. Researchers assessed inflammatory mediators via biochemical assays, anabolic gene expression using molecular analyses (qPCR), and extracellular matrix features through histological methods.

In 3D pellet cultures, liraglutide demonstrated potent anti-inflammatory effects. It significantly reduced IL-8 levels to 877.8 ± 155.3 ng at 0.5 µM compared to 3127.0 ± 1140.5 ng in IL-1β treated controls by day 14. A smaller, but notable, reduction was also observed for IL-6 levels, dropping to 863.6 ± 63.1 ng at 0.5 µM from 1055.0 ± 74.4 ng in the IL-1β group. Beyond inflammation, liraglutide promoted anabolic activity, increasing ACAN expression by 1.297 ± 0.820-fold compared to 0.260 ± 0.323-fold in IL-1β controls at lower concentrations. PRG4 expression was also higher at day 14 with increased concentrations, reaching 0.713 ± 0.07-fold versus 0.338 ± 0.11-fold in controls. In scaffold cultures under mechanical loading, liraglutide reduced IL-8 protein release at early time points by 3.782 ± 1.505-fold compared to 10.44 ± 6.524-fold in the IL-1β group, and was associated with donor-dependent modulation of ACAN expression (1.09 ± 0.84-fold vs 0.45 ± 0.13-fold).