Activation of NRF2 by celastrol increases antioxidant functions and prevents the progression of osteoarthritis in mice

IF 4 2区 医学 Q1 INTEGRATIVE & COMPLEMENTARY MEDICINE
Mingming LIU , Jiatian GUO , Jing ZHAO , Hongye LI , Xiaoxiao FENG , Haojun LIU , Hao ZHANG , Xuejun JIA , Rushuai WEI , Fang LI , Chong CHEN , Mingzhuang HOU , Nanning LV , Haiyan XU
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引用次数: 0

Abstract

Excessive oxidative stress impairs cartilage matrix metabolism balance, significantly contributing to osteoarthritis (OA) development. Celastrol (CSL), a drug derived from Tripterygium wilfordii, has recognized applications in the treatment of cancer and immune system disorders, yet its antioxidative stress mechanisms in OA remain underexplored. This study aimed to substantiate CSL's chondroprotective effects and unravel its underlying mechanisms. We investigated CSL's impact on chondrocytes under both normal and inflammatory conditions. In vitro, CSL mitigated interleukin (IL)-1β-induced activation of proteinases and promoted cartilage extracellular matrix (ECM) synthesis. In vivo, intra-articular injection of CSL ameliorated cartilage degeneration and mitigated subchondral bone lesions in OA mice. Mechanistically, it was found that inhibiting nuclear factor erythroid 2-related factor 2 (NRF2) abrogated CSL-mediated antioxidative functions and exacerbated the progression of OA. This study is the first to elucidate the role of CSL in the treatment of OA through the activation of NRF2, offering a novel therapeutic avenue for arthritis therapy.

芹甾醇激活 NRF2 可增强抗氧化功能并预防小鼠骨关节炎的恶化
过度的氧化应激会损害软骨基质代谢的平衡,从而在很大程度上导致骨关节炎(OA)的发生。Celastrol (CSL) 是一种从威灵仙提取的药物,已被公认可用于治疗癌症和免疫系统疾病,但其在 OA 中的抗氧化应激机制仍未得到充分探索。本研究旨在证实 CSL 的软骨保护作用,并揭示其潜在机制。我们研究了 CSL 在正常和炎症条件下对软骨细胞的影响。在体外,CSL 可减轻白细胞介素(IL)-1β 诱导的蛋白酶活化,促进软骨细胞外基质(ECM)的合成。在体内,关节内注射 CSL 可改善 OA 小鼠的软骨退化并减轻软骨下骨损伤。从机理上讲,研究发现抑制核因子红细胞2相关因子2(NRF2)会削弱CSL介导的抗氧化功能,并加剧OA的恶化。这项研究首次阐明了CSL通过激活NRF2在治疗OA中的作用,为关节炎治疗提供了一条新的治疗途径。
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来源期刊
Chinese Journal of Natural Medicines
Chinese Journal of Natural Medicines INTEGRATIVE & COMPLEMENTARY MEDICINE-PHARMACOLOGY & PHARMACY
CiteScore
7.50
自引率
4.30%
发文量
2235
期刊介绍: The Chinese Journal of Natural Medicines (CJNM), founded and sponsored in May 2003 by China Pharmaceutical University and the Chinese Pharmaceutical Association, is devoted to communication among pharmaceutical and medical scientists interested in the advancement of Traditional Chinese Medicines (TCM). CJNM publishes articles relating to a broad spectrum of bioactive natural products, leading compounds and medicines derived from Traditional Chinese Medicines (TCM). Topics covered by the journal are: Resources of Traditional Chinese Medicines; Interaction and complexity of prescription; Natural Products Chemistry (including structure modification, semi-and total synthesis, bio-transformation); Pharmacology of natural products and prescription (including pharmacokinetics and toxicology); Pharmaceutics and Analytical Methods of natural products.
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