1. Targeting YAP1-regulated Glycolysis in Fibroblast-Like Synoviocytes Impairs Macrophage Infiltration to Ameliorate Diabetic Osteoarthritis Progression.
- Author
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Yang J, Li S, Li Z, Yao L, Liu M, Tong KL, Xu Q, Yu B, Peng R, Gui T, Tang W, Xu Y, Chen J, He J, Zhao K, Wang X, Wang X, Zha Z, and Zhang HT
- Subjects
- Humans, Mice, Animals, Macrophages metabolism, Transcription Factors metabolism, Adaptor Proteins, Signal Transducing metabolism, Fibroblasts metabolism, Glycolysis, Synoviocytes metabolism, Synoviocytes pathology, Osteoarthritis metabolism, Diabetes Mellitus metabolism
- Abstract
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., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)
- Published
- 2024
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