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Background: Osteoarthritis (OA) is widely recognized as the most common chronic joint disease accompanied by progressive cartilage and subchondral bone damage. Toddalolactone (TOD), a natural compound extracted from Toddalia asiatica (L.) Lam., has been widely used in the treatment of stroke, rheumatoid arthritis, and oedema. Nevertheless, what TOD acts as in the pathogenesis and progression of OA hasn't been reported. In this investigation, we have aimed to determine how TOD affects OA in vitro and in vivo. Methods: LPS (10 µg/ml) and IL-1β (10 ng/ml) were employed to induce chondrocyte inflammation or RANKL to induce osteoclast differentiation in bone marrow derived macrophages (BMMs). The effects of TOD on chondrocyte inflammation and osteoclast differentiation were evaluated. Anterior cruciate ligament transection (ACLT) was performed to develop an OA animal model and study the effects of TOD. Results: We found that TOD inhibited the expression of inflammatory and catabolic mediators (IL-6, IL-8, TNF-α, MMP2, MMP9, and MMP13) in inflammatory chondrocytes in vitro. Furthermore, TOD was proven to inhibit RANKL-induced-osteoclastogenesis and inhibit the expression of osteoclast marker genes. Our data also confirmed that TOD suppressed the destruction of articular cartilage and osteoclastogenesis via inhibiting the activation of NF-κB and MAPK signalling pathways. In the ACLT mouse model, we found that TOD attenuated cartilage erosion and inhibited bone resorption. Conclusions: These results showed that TOD can be adopted as a potential therapeutic agent for OA. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is generally considered to be characterized by progressive articular cartilage destruction. Increasing evidence demonstrates that CDK9, which is a member of cyclin-dependent kinase family, plays a significant role in the regulation of acute and chronic inflammatory diseases. IL-1β, a major proinflammatory cytokine, was used to establish a model of OA in vitro after stimulating chondrocytes. We found that CDK9 was highly expressed in in vitro and in vivo models of inflammation. The role of LDC000067 (abbreviated as LDC067), a specific inhibitor of CDK9, in protecting articular cartilage from immune response has not been fully clarified. Intriguingly, in this study, we demonstrated that LDC067 prevented IL-1β-induced production of metalloproteinases (MMPs) and inflammatory cytokines, including MMP3, MMP9, MMP13, IL-6, IL-8 and TNF-ɑ. Furthermore, we revealed that LDC067 inhibited IL-1β-induced NF-κB signaling pathway activation in chondrocytes. The inhibition of CDK9 could also delay cartilage degeneration in an anterior cruciate ligament transection (ACLT) mouse model in vivo. Taken together, these results highlighted the significance of this CDK9 inhibitor in preventing cartilage destruction and indicated that LDC067 might serve as a potential therapeutic agent for OA. • CDK9 is upregulated in osteoarthritis cartilage and is correlated with the severity of OA. • The specific inhibitor of CDK9, LDC067 attenuates the catabolism and hypertrophic changes of chondrocytes in vitro. • LDC067 suppresses the activation of the NF-κB signaling pathway. • LDC067 ameliorates OA cartilage destruction in vivo and may be a novel therapeutic agent. [ABSTRACT FROM AUTHOR]

[Display omitted] • Spermidine increases BRG1 in osteoarthritic knee cartilage. • BRG1 mediates protective effects of spermidine on osteoarthritic cartilage. • BRG1 regulates Nrf2/KEAP1 and STAT3 signaling pathways, thereby participating in spermidine's ability to improve knee cartilage in osteoarthritis. • Spermidine may be an effective agonist for BRG1 and a potential agent for the treatment of osteoarthritis. Spermidine (SPD) is a natural polyamine that shows beneficial effects on osteoarthritis (OA). However, the effect of SPD on cartilage inflammation remains unknown. This study aimed to investigate the potential mechanisms underlying the protective effect of SPD against OA-induced articular cartilage degradation. SW1353 human chondrocytes were treated with hydrogen peroxide and lipopolysaccharide to induce models of inflammation and oxidative stress, followed by different dose of SPD intervention. Moreover, mice that underwent anterior cruciate ligament transection were bred and treated with SPD. The effects of SPD were observed using a CCK-8 kit, real-time polymerase chain reaction, immunoblotting, and immunofluorescent assays. SPD significantly increased the expression of antioxidant proteins, chondrogenic genes, and inflammatory factors both in vivo and in vitro. And injury of the mouse cartilage was also reduced by SPD. Moreover, SPD activated the Nrf2/KEAP1 pathway and inhibited STAT3 phosphorylation. BRG1 expression was decreased in osteoarthritic mouse cartilage, whereas SPD treatment caused an upregulation. However, when BRG1 was specifically inhibited by an adeno-associated virus and small interfering RNA, the antioxidant and anti-inflammatory effects of SPD were significantly diminished both in vitro and in vivo. We found that SPD ameliorated cartilage damage in OA by activating the BRG1-mediated Nrf2/KEAP1 pathway. SPD and BRG1 may provide new therapeutic options or targets for the treatment of OA. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) has traditionally been defined as a non-inflammatory disease. Recently, many studies have demonstrated that OA also has an inflammatory component. BRD4, a member of the Bromodomain and Extra-Terminal Domain family, has emerged as an important regulator of some chronic inflammatory diseases. JQ1, an antagonist of BRD4, modulates transcription of several genes. Our study demonstrated that BRD4 is up-regulated in articular cartilage of OA. BRD4 inhibition attenuated the inflammation and catabolism of chondrocytes and suppressed NF-κB signalling pathway activation. In addition, BRD4 inhibition abolished the transcriptional activity of High Mobility Group Protein B1 (HMGB1). We identified HMGB1 as a direct target of BRD4. Genetic and pharmacological inhibition of BRD4 suppressed IL-1β-induced expression and translocation of HMGB1. Chromatin immunoprecipitation (ChIP) showed the enrichment of BRD4 around the HMGB1 upstream non-promoter region, which diminished with JQ1 treatment. Finally, haematoxylin & eosin and Safranin o/Fast Green staining demonstrated that JQ1 attenuates cartilage destruction in mice with anterior cruciate ligament transection without significant toxic effects. These studies highlighted the importance of BRD4 in the chronic inflammatory reactions of OA, which, as far as we know, was the first report of this finding, and suggested that BRD4 might be a novel potential therapeutic target for the treatment of OA. [ABSTRACT FROM AUTHOR]

• EsA attenuates inflammation and catabolism of chondrocytes. • EsA restrains RANKL-induced osteoclast formation. • Treatment with EsA suppresses NF-κB and MAPK signalling pathway activation in vitro. • EsA protects OA cartilage in vivo and may be a novel therapeutic target. Osteoarthritis is a relatively common disorder of articular deterioration related to cartilage damage, subchondral bone remodelling, inflammation and metabolism. Agents that can inhibit cartilage degradation and osteoclastogenesis are required for the prevention and treatment of osteoarthritis. Esculentoside A, the highest concentration triterpene saponin isolated from the root of Phytolacca esculenta, has commonly been used for the treatment of chronic bronchitis. However, the role esculentoside A plays in ameliorating osteoarthritis has not been reported. We found that esculentoside A suppresses the expression of IL-1β-induced inflammatory and metabolic factors (IL-6, IL-8, TNF-α, MMP2, MMP3 and MMP13). In addition, esculentoside A restrains osteoclast formation by inhibiting the marker gene expression of NFATc1 and c-Fos. Our results indicate that esculentoside A markedly suppresses IL-1β-induced NF-κB and MAPK signalling pathway activation in chondrocytes, and inhibits RANKL-induced osteoclast precursor generation. Finally, treatment with esculentoside A inhibits the progressive cartilage degeneration and osteoclastogenesis in osteoarthritis mouse models. In summary, these results demonstrate that esculentoside A could be a latent therapeutic reagent for the treatment of osteoarthritis. [ABSTRACT FROM AUTHOR]