Disease Modifying Osteoarthritis Drug Discovery Using a Temporal Phenotypic Reporter in 3D Aggregates of Primary Human Chondrocytes

The study aimed to discover disease-modifying drugs for osteoarthritis by focusing on stimulating type II collagen anabolism in chondrocytes. Researchers developed a novel approach using primary human chondrocytes expressing Gaussia luciferase under the type II collagen promoter, cultured in 3D aggregates. Over 3 weeks, a natural product library was screened, identifying aromoline as a promising compound. Aromoline, a bisbenzylisoquinoline alkaloid, increased type II collagen expression in chondrocytes from three donors. In silico analysis suggested the dopamine receptor D4 (DRD4) as a target, confirmed by upregulation of type II collagen with aromoline and DRD4-specific agonist ABT-724. This approach offers a platform for drug discovery in osteoarthritis, identifying aromoline and DRD4 as potential therapeutic targets.