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.

Effects of limonin treatment on the survival of random skin flaps in mice

“…As reported, limonin was able to alleviate hepatocellular injury following liver ischemia and reperfusion, and the mechanism of these hepatoprotective effects appears to be related to the antioxidant and anti-in ammatory potential of limonin through toll-like receptor dependent pathway [11]. In addition, it has also been shown that limonin inhibited IL-1β-induced in ammation and catabolism responses in chondrocytes and attenuates the development of osteoarthritis, indicating its signi cant effect of anti-in ammation [12]. Considering the potent effect of limonin on anti-in ammatory and antioxidant, and ischemia related diseases, we wonder that limonin may protects against ischemia and necrosis on random skin aps.…”

Limonin stabilises sirtuin 6 (SIRT6) by activating ubiquitin specific peptidase 10 (USP10) in cardiac hypertrophy

“…Consistently, limonin reduced the mRNA levels of hypertrophic genes ( Nppb , Myh7 and Acta1 ) and pro‐fibrotic genes ( Col1a1 and Col3a1 ) and increased Myh6 after aortic banding operation (Figure 2l–q). Given the anti‐inflammatory effects of limonin in another disease model (Jin et al, 2021; Yang et al, 2020), we also analysed the level of inflammation in the presence of limonin. In aortic banding‐induced hypertrophic hearts, limonin decreased interleukin‐1 beta (IL‐1β) and tumour necrosis factor (Tnf) mRNA levels (Figure S1c,d).…”

“…As shown in 2l-q). Given the anti-inflammatory effects of limonin in another disease model (Jin et al, 2021;Yang et al, 2020), we also analysed the level of inflammation in the presence of limonin.…”

Omaveloxolone inhibits IL-1β-induced chondrocyte apoptosis through the Nrf2/ARE and NF-κB signalling pathways in vitro and attenuates osteoarthritis in vivo

“…The cell viability of chondrocytes was measured using a Cell Counting Kit-8 (CCK-8, Beyotime Institute of Biotechnology, Shanghai, China). Cells were treated with different concentrations of omaveloxolone (5, 10, 25, 50, 100, 250, 500, 1000 and 2000 nM) for 24, 48 and 72 h. IL-1β (10 ng/ml, PeproTech EC, London, United Kingdom) was used to mimic inflammatory conditions ( Jin et al, 2021 ). DMEM containing 10% CCK-8 solution was added to each well for 2 h. Absorption was detected at 450 nm using a microplate reader (Epoch; BioTek Instruments Inc., Vermont, United States).…”