<br>靶向成纤维细胞样滑膜细胞中 YAP1 调节的糖酵解可损害巨噬细胞浸润，从而改善糖尿病骨关节炎进展,Advanced Science

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靶向成纤维细胞样滑膜细胞中 YAP1 调节的糖酵解可损害巨噬细胞浸润，从而改善糖尿病骨关节炎进展
Advanced Science ( IF 14.3 ) Pub Date : 2023-12-03 , DOI: 10.1002/advs.202304617
Jie Yang ₁ , Shanshan Li ₂ , Zhenyan Li ₁ , Lutian Yao ₃ , Meijing Liu _{4,

5} , Kui-Leung Tong ₁ , Qiutong Xu ₁ , Bo Yu ₁ , Rui Peng ₁ , Tao Gui ₁ , Wang Tang ₁ , Yidi Xu ₁ , Jiaxu Chen ₆ , Jun He ₇ , Kewei Zhao ₈ , Xiaogang Wang _{4,

5} , Xiaoying Wang ₂ , Zhengang Zha ₁ , Huan-Tian Zhang _{1,

8}

Affiliation

Department of Bone and Joint Surgery, the First Affiliated Hospital of Jinan University, Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, Guangdong, 510630, China.
State Key Laboratory of Pulp and Paper Engineering, South China University of Technology, Guangzhou, 510640, China.
Department of Orthopedics, The First Hospital of China Medical University, Shenyang, 110001, China.
Key Laboratory of Big Data-Based Precision Medicine, School of Engineering Medicine, Beihang University, Beijing, 100191, China.
Clinical Research Platform for Interdisciplinary of Stomatology, the First Affiliated Hospital of Jinan University and Department of Stomatology, Jinan University, Guangzhou, 510632, China.
Guangzhou Key Laboratory of Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510640, China.
Institute of Laboratory Animal Science, Jinan University, Guangzhou, 510632, China.
Guangzhou Key Laboratory of Chinese Medicine Research on Prevention and Treatment of Osteoporosis, the Third Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510375, China.

免疫细胞/巨噬细胞与成纤维细胞样滑膜细胞 (FLS) 之间的相互作用在引发滑膜炎中发挥着关键作用；然而，它们与代谢紊乱（包括糖尿病骨关节炎（DOA））的关系在很大程度上尚不清楚。在本研究中，采用单细胞 RNA 测序 (scRNA-seq) 来研究 DOA 滑膜细胞的组成。在 DOA 滑膜中发现八个不同的滑膜细胞簇内活化的巨噬细胞显着富集。此外，研究表明，FLS 中糖酵解的增加是 DOA 患者滑膜巨噬细胞浸润和极化的关键驱动因素。此外，yes相关蛋白1（YAP1）/硫氧还蛋白相互作用蛋白（TXNIP）信号轴被证明在调节FLS中葡萄糖转运蛋白1（GLUT1）依赖性糖酵解中发挥着至关重要的作用，从而控制一系列细胞间粘附分子-1 (ICAM-1) 等粘附分子可能随后微调 DOA 患者和db/db糖尿病 OA 小鼠中 M1 极化滑膜巨噬细胞的浸润。在治疗方面，开发了 M1 巨噬细胞膜伪装的维替泊芬 (Vt) 负载 PLGA 纳米颗粒 (MVP)，通过调节 YAP1/TXNIP 信号轴来改善 DOA 进展，从而抑制滑膜糖酵解和 M1 极化巨噬细胞的浸润。这些结果为 DOA 的发病机制提供了一些新的见解，并为 DOA 提供了一种有前景的治疗方法。

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

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.

更新日期：2023-12-03

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