Molecular dynamics simulation files for: a molecular machine efficiently drives glycosaminoglycan assembly and secretion for osteoarthritis therapy

Osteoarthritis (OA), the most prevalent form of arthritis, affects 500
million people worldwide and is characterized by an irreversible loss of
glycosaminoglycans (GAGs) at articular 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. Particularly, HDMBr promoted 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 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.

骨关节炎（Osteoarthritis, OA）是全球最常见的关节炎类型，影响人群逾5亿，其病理特征为关节表面糖胺聚糖（glycosaminoglycans, GAGs）发生不可逆流失。尽管相关研究已取得一定进展，但在活体细胞中保留软骨糖胺聚糖并调控其代谢仍极具挑战。
基于“糖胺聚糖可与阳离子分子相互作用”这一假说，本研究开发了一种经济高效的策略：借助分子机器溴化己二甲铵（hexadimethrine bromide, HDMBr）提升人体软骨内的糖胺聚糖含量。HDMBr可通过募集细胞周糖胺聚糖、上调囊泡形成过程，促进干细胞软骨分化，进而增加软骨基质分泌。尤为关键的是，HDMBr可在细胞内运输阶段推动硫酸软骨素（chondroitin sulfate, CS）组装为高浓缩凝聚体，从而实现糖胺聚糖的高效分泌。
随后，本研究在两种动物模型中评估了HDMBr的治疗潜力：在大体积软骨缺损兔模型中，HDMBr可促进内源性富含糖胺聚糖的透明样软骨再生，并改善组织整合效果；在大鼠骨关节炎模型中，低剂量HDMBr治疗可增加软骨厚度、维持软骨基质稳态，并提升细胞治疗的效率，相较于其他受试临床治疗方案，可显著延缓骨关节炎进展。
总体而言，本研究提出了一种经济高效的糖胺聚糖调控方法，用于软骨修复与关节保护，为解析细胞-材料相互作用机制提供了全新视角。