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

ABSTRACT: Osteoarthritis (OA) affects nearly 500 million people worldwide and is characterized by an irreversible loss of glycosaminoglycans (GAGs) at articular cartilage surfaces. Despite advances, preserving cartilage GAGs and controlling their turnover in living cells remain challenging. Based on the hypothesis that GAGs can interact with cationic molecules, we demonstrated a cost-effective strategy to increase human cartilage GAGs using a molecular machine hexadimethrine bromide (HDMBr). HDMBr promoted stem cell chondrogenesis by attracting pericellular GAGs and upregulating vesicle formation, leading to increased matrix secretion. To determine how HDMBr influenced cellular protein expression, we performed proteomics by mass spectrometry on cultured human mesenchymal stem cells. Based on the results, HDMBr induced widespread proteomic changes and might stimulate intracellular GAG metabolism, intracellular trafficking, and GAG secretion. The proteomics data were also consistent with the evaluation of HDMBr 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 OA model, low-dose HDMBr treatment increased cartilage thickness, supported cartilage matrix homeostasis, and improved the efficiency of cell-based therapy, evidently slowing OA progression compared to other tested clinical treatments. Overall, this study introduces a cost-effective GAG manipulation approach to cartilage repair and joint preservation, offering new insights into the mechanisms of cell-material interactions.

ORGANISM(S): Homo Sapiens

SUBMITTER: Hongwei Ouyang

PROVIDER: PXD063645 | iProX | Thu May 01 00:00:00 BST 2025

REPOSITORIES: iProX

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

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