Lacc1-engineered extracellular vesicles reprogram mitochondrial metabolism to alleviate inflammation and cartilage degeneration in TMJ osteoarthritis.

IF 10.6 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Xiaofeng Hu, Jian Xie, Jiansheng Su
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引用次数: 0

Abstract

Temporomandibular joint osteoarthritis (TMJOA) is a multifaceted degenerative disease characterized by progressive cartilage degradation, chronic pain, and functional limitations of the TMJ, significantly affecting patients' quality of life. Although metabolic homeostasis in chondrocytes is crucial for cartilage health, the mechanisms underlying metabolic dysregulation in TMJOA remain poorly characterized. This study aimed to investigate the metabolic imbalance in TMJOA cartilage and explore novel therapeutic strategies targeting metabolic reprogramming. RNA sequencing revealed a significant imbalance between glycolysis and oxidative phosphorylation (OXPHOS) in TMJOA cartilage, with a marked shift toward glycolysis, which is associated with inflammation and cartilage degradation. To counteract this imbalance, Laccase domain-containing 1 (Lacc1), a metabolic regulator involved in both inflammation and metabolic homeostasis, was selected for investigation, as its role in chondrocytes had not been explored. We engineered macrophage-derived extracellular vesicles (EVs) to overexpress Lacc1 (OE-EVs), aiming to restore metabolic balance and modulate inflammation in chondrocytes. In vitro, OE-EVs significantly reduced IL-1β-induced inflammation, inhibited glycolysis by decreasing key glycolytic enzymes, improved mitochondrial function by decreasing mitochondrial superoxide levels, and the restoration of normal mitochondrial structure. In vivo, micro-computed tomography (Micro-CT) and histological analyses demonstrated that OE-EVs effectively alleviated inflammation and promoted cartilage repair, as indicated by a 1.55-fold increase in toluidine blue-stained cartilage area compared to the TMJOA group, reflecting improved cartilage matrix integrity and proteoglycan retention. These findings highlight the therapeutic potential of Lacc1-engineered EVs to target mitochondrial metabolism, reestablish metabolic homeostasis, and reduce inflammation in TMJOA, offering a novel and promising strategy for improving clinical outcomes in TMJOA patients.

Lacc1设计的细胞外囊泡重新规划线粒体代谢,缓解颞下颌关节骨关节炎的炎症和软骨退化。
颞下颌关节骨性关节炎(TMJOA)是一种以进行性软骨退化、慢性疼痛和TMJ功能限制为特征的多方面退行性疾病,严重影响患者的生活质量。尽管软骨细胞的代谢稳态对软骨健康至关重要,但TMJOA代谢失调的机制仍不清楚。本研究旨在研究TMJOA软骨的代谢失衡,并探索针对代谢重编程的新治疗策略。RNA测序显示,TMJOA软骨中糖酵解和氧化磷酸化(OXPHOS)之间存在明显的不平衡,糖酵解明显偏向于糖酵解,这与炎症和软骨降解有关。为了抵消这种不平衡,漆酶结构域1 (Lacc1),一种参与炎症和代谢稳态的代谢调节因子,被选中进行研究,因为它在软骨细胞中的作用尚未被探索。我们设计巨噬细胞来源的细胞外囊泡(EVs)来过表达Lacc1 (e- EVs),旨在恢复代谢平衡和调节软骨细胞的炎症。在体外,oe - ev可显著降低il -1β诱导的炎症,通过降低关键糖酵解酶抑制糖酵解,通过降低线粒体超氧化物水平改善线粒体功能,恢复正常线粒体结构。在体内,微计算机断层扫描(Micro-CT)和组织学分析表明,oe - ev有效缓解炎症,促进软骨修复,甲苯胺蓝染色的软骨面积比TMJOA组增加1.55倍,反映了软骨基质完整性和蛋白聚糖潴留的改善。这些发现突出了lacc1工程ev靶向线粒体代谢、重建代谢稳态和减少TMJOA炎症的治疗潜力,为改善TMJOA患者的临床结果提供了一种新颖而有前途的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Nanobiotechnology
Journal of Nanobiotechnology BIOTECHNOLOGY & APPLIED MICROBIOLOGY-NANOSCIENCE & NANOTECHNOLOGY
CiteScore
13.90
自引率
4.90%
发文量
493
审稿时长
16 weeks
期刊介绍: Journal of Nanobiotechnology is an open access peer-reviewed journal communicating scientific and technological advances in the fields of medicine and biology, with an emphasis in their interface with nanoscale sciences. The journal provides biomedical scientists and the international biotechnology business community with the latest developments in the growing field of Nanobiotechnology.
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