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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]

Objectives: Aseptic loosening (AL) is the most common reason of total hip arthroplasty (THA) failure and revision surgery. Osteolysis, caused by wear particles released from implant surfaces, has a vital role in AL. Although previous studies suggest that wear particles always lead to osteoblast programmed death in the process of AL, the specific mechanism remains incompletely understood and osteoblast ferroptosis maybe a new mechanism of AL. Materials and Methods: CoCrMo nanoparticles (CoNPs) were prepared to investigate the influence of ferroptosis in osteoblasts and calvaria resorption animal models. Periprosthetic osteolytic bone tissue was collected from patients who underwent AL after THA to verify osteoblast ferroptosis. Results: Our study demonstrated that CoNPs induced significant ferroptosis in osteoblasts and particles induced osteolysis (PIO) animal models. Blocking ferroptosis with specific inhibitor Ferrostatin‐1 dramatically reduced particle‐induced ferroptosis in vitro. Moreover, in osteoblasts, CoNPs significantly downregulated the expression of Nrf2 (nuclear factor erythroid 2‐related factor 2), a core element in the antioxidant response. The overexpression of Nrf2 by siKeap1 or Nrf2 activator Oltipraz obviously upregulated antioxidant response elements (AREs) and suppressed ferroptosis in osteoblasts. Furthermore, in PIO animal models, the combined utilization of Ferrostatin‐1 and Oltipraz dramatically ameliorated ferroptosis and the severity of osteolysis. Conclusions: These results indicate that CoNPs promote osteoblast ferroptosis by regulating the Nrf2‐ARE signalling pathway, which suggests a new mechanism underlying PIO and represents a potential therapeutic approach for AL. [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]