Targeting YAP1-regulated Glycolysis in Fibroblast-Like Synoviocytes Impairs Macrophage Infiltration to Ameliorate Diabetic Osteoarthritis Progression

作者：Yang, Jie; Li, Shanshan; Li, Zhenyan; Yao, Lutian; Liu, Meijing; Tong, Kui-Leung; Xu, Qiutong; Yu, Bo; Peng, Rui; Gui, Tao; Tang, Wang; Xu, Yidi; Chen, Jiaxu; He, Jun; Zhao, Kewei; Wang, Xiaogang; Wang, Xiaoying^*; Zha, Zhengang^*; Zhang, Huan-Tian^*

来源：Advanced Science, 2023.

DOI：10.1002/advs.202304617

• diabetic osteoarthritis
• fibroblast-like synoviocytes
• glycolysis
• macrophages infiltration
• YAP1

The interplay between immune cells/macrophages and fibroblast-like synoviocytes (FLSs) plays a pivotal role in initiating synovitis; however, their involvement in metabolic disorders, including diabetic osteoarthritis (DOA), is largely unknown. In this study, single-cell RNA sequencing (scRNA-seq) is employed to investigate the synovial cell composition of DOA. A significant enrichment of activated macrophages within eight distinct synovial cell clusters is found in DOA synovium. Moreover, it is demonstrated that increased glycolysis in FLSs is a key driver for DOA patients' synovial macrophage infiltration and polarization. In addition, the yes-associated protein 1 (YAP1)/thioredoxin-interacting protein (TXNIP) signaling axis is demonstrated to play a crucial role in regulating glucose transporter 1 (GLUT1)-dependent glycolysis in FLSs, thereby controlling the expression of a series of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) which may subsequently fine-tune the infiltration of M1-polarized synovial macrophages in DOA patients and db/db diabetic OA mice. For treatment, M1 macrophage membrane-camouflaged Verteporfin (Vt)-loaded PLGA nanoparticles (MVPs) are developed to ameliorate DOA progression by regulating the YAP1/TXNIP signaling axis, thus suppressing the synovial glycolysis and the infiltration of M1-polarized macrophages. The results provide several novel insights into the pathogenesis of DOA and offer a promising treatment approach for DOA. @@@ Enrichment of M1 macrophage and enhanced glycolysis of fibroblast-like synoviocytes (FLSs) play key roles in pathogenesis of diabetic osteoarthritis (DOA). Mechanistically, yes-associated protein 1 (YAP1)/thioredoxin-interacting protein (TXNIP) signaling axis regulates the glycolysis of FLSs thus fine-tuning the M1 macrophage recruitment and infiltration. Furthermore, M1 macrophage membrane-camouflaged Vt-loaded nanoparticles could significantly alleviate the DOA by suppressing the YAP1/TXNIP signaling regulated synovial glycolysis and M1 macrophages infiltration. image

• 单位
  北京航空航天大学; 广州中医药大学; 1; 中国医科大学