Abstract
Articular cartilage injury or defect is a common disease and is mainly characterized by cartilage degradation because of chondrocyte inflammation. By now, there are no effective drugs and methods to protect articular cartilage from degradation. Icariin (ICA) is a typical flavonoid compound extracted from Epimedii Folium with anti-inflammatory and bone-protective effects. Our previous studies demonstrate that ICA up-regulates HIF-1α expression and glycolysis in chondrocytes and maintains chondrocyte phenotype. As another member of HIFs family, HIF-2α always plays a key role in inflammation. The effect of ICA on HIF-2α is unclear by now. In the present study, we confirmed the findings in our previous study that ICA promoted not only chondrocyte vitality and extracellular matrix (ECM) synthesis, but also the anti-inflammatory effect of ICA. In bone defect mice, ICA inhibited the expressions of NF-κB and HIF-2α. In TNF-α-treated ADTC5 chondrocytes, ICA neutralized the activation of IKK (IKK phosphorylation), the phosphorylation of IkB and NF-κB and the expression of HIF-2α. Furthermore, ICA inhibited the nucleus transfer of NF-κB and the expressions of MMP9 and ADAMTS5, two key targets of NF-κB/HIF-2α signal pathway. Taken together, the present study demonstrated that ICA may increase the vitality of chondrocytes by suppressing the inflammatory injury through the inhibition on NF-κB/HIF-2α signaling pathway. ICA is one effective candidate drug for the treatment of articular cartilage injury.
Highlights
Articular cartilage is a highly organized avascular connective tissue with limited regenerative ability following trauma or degenerative pathology [1]
Basing on our previous study [20] and this, 20 ng/ml of TNF-α was used as an inflammation inducer and 10−6 mol/l of ICA was used in the subsequent experiments in chondrocytes
By H & E and SO staining, we found that the cartilage surface was relatively intact and the subchondral bone was substantial in the alginate-gelfoam-ICA group; while in the alginate-gelfoam-Con group, the cartilage layer was thin, rough, and less matrix staining (Figure 1E). Consistent with these findings, the International Cartilage Repair Society (ICRS) II score of matrix staining, subchondral bone and overall assessment in the alginate-gelfoam-ICA group was significantly increased comparing with the alginate-gelfoam-Con group (Figure 1F). These findings indicated that ICA relieved extracellular matrix (ECM) degradation and the destruction of articular cartilage and suppressed cartilage degradation in mice
Summary
Articular cartilage is a highly organized avascular connective tissue with limited regenerative ability following trauma or degenerative pathology [1]. The pathological features of cartilage damage are chondrocyte apoptosis, aging and the reduction of extracellular matrix (ECM) synthesis. In addition to other considerations such as aging, common cartilage injuries are caused by mechanical traumas [4]. The release of proinflammatory cytokines driven by mechanical injury is an important factor in the process of cartilage damage evolved into inflammation and osteoarthritis (OA) [5]. These inflammatory mediators, including TNF-α and IL-1β, are catabolic cytokines involved in the degradation of ECM by promoting the expression of matrix MMPs and ADAMTS [6]. TNF-α increases the cartilage degeneration through the activation of NF-κB and PI3K/AKT [8]
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