A cationic polymer drives glycosaminoglycan assembly and secretion for preclinical osteoarthritis therapy

Osteoarthritis (OA) affects nearly 500 million people worldwide and is characterized by an irreversible loss of glycosaminoglycans (GAGs) at articular cartilage surfaces, which are essential in maintaining cartilage mechanical properties and chondrocyte phenotypes. Despite advances, preserving cartilage GAGs and controlling their turnover in living cells remain challenging. On the basis of the hypothesis that GAGs can interact with cationic molecules, we demonstrated a cost-effective strategy to increase human cartilage GAGs using a cationic polymer hexadimethrine bromide (HDMBr). HDMBr promoted chondrogenesis of mesenchymal stem cells by attracting pericellular GAGs and up-regulating vesicle formation, leading to increased matrix secretion. HDMBr also acted like a molecular assembler to promote the assembly of chondroitin sulfate (CS) into highly concentrated condensates during intracellular trafficking, resulting in more efficient GAG secretion. HDMBr was then evaluated as a potential therapeutic in two animal models. In a rabbit model of large cartilage defects, HDMBr promoted the intrinsic regeneration of GAG-rich hyaline-like cartilage and improved tissue integration. In a rat model of OA, low-dose HDMBr treatment increased cartilage thickness, supported cartilage matrix homeostasis, and supported cell-based therapy, reducing OA damage as compared with other tested clinical treatments. Overall, this study introduces a cost-effective GAG manipulation approach to cartilage repair and joint preservation, offering insights into the mechanisms of cell-material interactions.