Abstract
Osteoarthritis (OA), characterized by chronic systemic low-level inflammation and cartilage degeneration, is a type of arthritis closely associated with aging. Inflammation and aging play a pivotal role in the occurrence and progression of OA. NLRP3 inflammasome is involved in many inflammatory and aging diseases, and NLRP3 inhibitor MCC950 has anti-inflammatory and antisenescence effects on some diseases such as Alzheimer's disease. In the present study, we found that NLRP3 protein was upregulated in human and mouse OA cartilage. Moreover, NLRP3 and Caspase1 expression induced by IL-1β in chondrocytes was blocked by MCC950. In addition, MCC950 inhibited the expression of inflammatory mediators, matrix-degrading enzymes, senescence marker protein P16 (INK4A), and β-galactosidase, as well as excessive production of ROS. Meanwhile, MCC950 promoted autophagy-related protein expression and autophagy flux under the inflammatory condition. However, autophagy inhibitor 3-MA reversed anti-inflammatory and anticatabolic effects of MCC950. In in vivo experiments, intra-articular administration of MCC950 further showed its protective effect on cartilage degeneration. Bioinformatic analysis and in vitro experimental results revealed that MCC950 might play a protective role in cartilage by regulating Nrf2/HO-1/NQO1, PI3k/Akt/mTOR, P38/MAPK, and JNK/MAPK pathways. In conclusion, our work demonstrated that NLRP3 inhibitor MCC950 might serve as a promising strategy for OA treatment.
Highlights
Osteoarthritis (OA) affects more than 250 million people worldwide, among which middle-aged and elderly people are vulnerable [1]
Substantial inflammatory factors were produced during the process of synovitis, contributing to the production of matrix-degrading enzymes and promoting cartilage degeneration [28]
NLRP3 inflammasome has been reported to be involved in hydroxyapatite-induced synovitis of the knee [30], and the application of NLRP3 inhibitor MCC950 can significantly ameliorate rheumatoid arthritis (RA) [22]
Summary
Osteoarthritis (OA) affects more than 250 million people worldwide, among which middle-aged and elderly people are vulnerable [1]. Joint pain, swelling, and stiffness are common symptoms in OA, in which inflammation and aging play a crucial role [3, 4]. Current clinical practices mainly rely on nonsteroidal anti-inflammatory drugs to relieve symptoms such as pain, while the drug-related cardiovascular and gastrointestinal side effects cannot be avoided. Low-grade systemic chronic inflammation is one of the main characteristics of OA [5]. Inflammatory factors such as IL-1β can induce matrix degradation, oxidative stress, cell senescence, and impaired autophagy in chondrocytes, leading to cartilage degeneration [6]. Inflammasomes play a vital role in the initiation and development of inflammation via promoting the maturation and secretion of IL-1β [7].
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