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Limonin Inhibits IL-1β-Induced Inflammation and Catabolism in Chondrocytes and Ameliorates Osteoarthritis by Activating Nrf2.

ABSTRACT: Osteoarthritis (OA), a degenerative disorder, is considered to be one of the most common forms of arthritis. Limonin (Lim) is extracted from lemons and other citrus fruits. Limonin has been reported to have anti-inflammatory effects, while inflammation is a major cause of OA; thus, we propose that limonin may have a therapeutic effect on OA. In this study, the therapeutic effect of limonin on OA was assessed in chondrocytes in vitro in IL-1β induced OA and in the destabilization of the medial meniscus (DMM) mice in vivo. The Nrf2/HO-1/NF-κB signaling pathway was evaluated to illustrate the working mechanism of limonin on OA in chondrocytes. In this study, it was found that limonin can reduce the level of IL-1β induced proinflammatory cytokines such as INOS, COX-2, PGE2, NO, TNF-α, and IL-6. Limonin can also diminish the biosynthesis of IL-1β-stimulated chondrogenic catabolic enzymes such as MMP13 and ADAMTS5 in chondrocytes. The research on the mechanism study demonstrated that limonin exerts its protective effect on OA through the Nrf2/HO-1/NF-κB signaling pathway. Taken together, the present study shows that limonin may activate the Nrf2/HO-1/NF-κB pathway to alleviate OA, making it a candidate therapeutic agent for OA.

SUBMITTER: Jin J

PROVIDER: S-EPMC8595032 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Limonin Inhibits IL-1β-Induced Inflammation and Catabolism in Chondrocytes and Ameliorates Osteoarthritis by Activating Nrf2.

Jin Jie J Lv Xinhuang X Wang Ben B Ren Chenghao C Jiang Jingtao J Chen Hongyu H Chen Ximiao X Gu Mingbao M Pan Zongyou Z Tian Naifeng N Wu Aimin A Sun Liaojun L Gao Weiyang W Wang Xiangyang X Zhang Xiaolei X Wu Yaosen Y Zhou Yifei Y

Oxidative medicine and cellular longevity 20211109

Osteoarthritis (OA), a degenerative disorder, is considered to be one of the most common forms of arthritis. Limonin (Lim) is extracted from lemons and other citrus fruits. Limonin has been reported to have anti-inflammatory effects, while inflammation is a major cause of OA; thus, we propose that limonin may have a therapeutic effect on OA. In this study, the therapeutic effect of limonin on OA was assessed in chondrocytes in vitro in IL-1β induced OA and in the destabilization of ...[more]

PMID: 34795843

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Project description:BackgroundDiscovering an inhibitor for acyl-CoA synthetase long-chain family member 4 (ACSL4), a protein that triggers cell injury via ferroptosis, presents potential to minimize cellular damage. This study investigates paeonol (PAE), a traditional Chinese herbal medicine, as an ACSL4 inhibitor to prevent chondrocyte ferroptosis and protect against osteoarthritis (OA).MethodsWe conducted in vitro experiments using mouse chondrocytes treated with PAE to mitigate ferroptosis induced by Interleukin-1 Beta (IL-1β) or ferric ammonium citrate (FAC), examining intracellular ferroptotic indicators, cartilage catabolic markers, and ferroptosis regulatory proteins. A mouse OA model was created via destabilized medial meniscus (DMM), followed by intra-articular PAE injections. After 8 weeks, micro-computed tomography and histological assessments evaluated PAE's protective and anti-ferroptotic effects in the OA model.ResultsIn vitro results showed PAE significantly reduced IL-1β/FAC-induced damage by targeting ACSL4, including cell apoptosis, inflammatory responses, extracellular matrix degradation, and ferroptotic markers (oxidative stress, lipid peroxidation, and iron buildup). It also restored the expression of ferroptotic suppressors and mitigated mitochondrial damage. Additionally, PAE increased cartilage anabolic marker expression while reducing cartilage catabolic marker expression. Molecular docking, cellular thermal shift assay, and drug affinity responsive target stability analysis verified the binding interaction between PAE and ACSL4. Furthermore, the role of PAE in chondrocytes was further verified through ACSL4 knockdown and overexpression. In vivo, mice with OA showed increased cartilage degradation and ferroptosis, while intra-articular PAE injection alleviated these pathological changes.ConclusionPAE significantly protects chondrocytes from ferroptosis induced by IL-1β/FAC in primary mouse chondrocytes and DMM surgery-induced OA mice through ACSL4 inhibition.The translational potential of this articleThese findings highlight the potential of targeting ACSL4 in chondrocytes as a treatment strategy for OA, positioning PAE as a promising drug candidate.

Dataset Information

Limonin Inhibits IL-1β-Induced Inflammation and Catabolism in Chondrocytes and Ameliorates Osteoarthritis by Activating Nrf2.

Publications

Limonin Inhibits IL-1<i>β</i>-Induced Inflammation and Catabolism in Chondrocytes and Ameliorates Osteoarthritis by Activating Nrf2.

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