Rapamycin protects chondrocytes against IL-18-induced apoptosis and ameliorates rat osteoarthritis

Abstract

Interleukin 18 (IL-18) promotes inflammation and apoptosis in chondrocytes, thereby contributing to the development and progression of osteoarthritis (OA). Here, we investigated the effects of IL-18 treatment and inhibition in rat chondrocytes in vitro and in vivo. We used RT-PCR and Western blotting to measure the mRNA and protein levels of the chondrocyte-specific genes Collagen II and Aggrecan as well as the protein levels of apoptosis-related (Bax, Bcl2, Caspase3/9), autophagy-related (Atg5, Atg7, Beclin1, LC3), and mTOR pathwayrelated genes (PI3K, Akt, mTOR). We observed a decrease in Collagen II and Aggrecan mRNA and protein levels, upregulation of chondrocyte apoptosis, downregulation of chondrocyte autophagy, and activation of the PI3K/Akt/mTOR pathway upon IL-18 treatment. PI3K/Akt/mTOR pathway activation and inhibition tests using rat 740Y-P (PI3K activator), SC79 (AKT activator), 3BDO (mTOR activator), or LY294002 (PI3K inhibitor) revealed that activation of the PI3K/Akt/mTOR pathway enhances chondrocyte-specific gene degradation induced by IL-18, while its inhibition has protective effects on chondrocytes. We also found that treatment with rapamycin (a selective mTOR inhibitor) also exerts chondro-protective effects that ameliorate OA by promoting autophagy. These results suggest that inhibition of the mTOR pathway could be exploited for therapeutic benefits in the treatment of OA.

Icariin alleviates osteoarthritis by regulating autophagy of chondrocytes by mediating PI3K/AKT/mTOR signaling

“…However, treatment with rapamycin significantly alleviated the pathological changes in the articular cartilage and head, and, notably, with an increase in icariin concentration, the pathological changes in the articular cartilage and head were ameliorated in a dose-dependent manner. The alleviation effect of rapamycin was also reported by Bao [34].…”

“…Furthermore, the results of immunofluorescence and western blotting assays (Figure 6(b,c)) showed that ATG7 and LC3-II/LC3-I levels were markedly lower in the OA group than in the sham group, but the levels were significantly upregulated after rapamycin treatment and increased in a dose-dependent manner after icariin treatment (**p < 0.01 vs. sham, ##p < 0.01 vs. OA). The autophagy-inducing effect of rapamycin in OA cartilage tissues has also been reported by Bao [34].…”

Rapamycin Treatment of Tendon Stem/Progenitor Cells Reduces Cellular Senescence by Upregulating Autophagy

“…Rapamycin was first approved in 1999 for allograft protection in kidney transplant recipients and approved in 2002 for the antirestenosis aspect for patients with coronary artery repairs [ 21 ]. In recent years, interests of rapamycin have been drawn to its potential as an anticancer drug, as well as its beneficial effects shown in a number of animal models of neurodegeneration and osteoarthritis [ 22 , 23 ]. Moreover, researchers have found the association of the mTOR pathway signaling activity with cellular and organismal aging [ 24 ].…”

Purinergic System Signaling in Metainflammation-Associated Osteoarthritis

“…IL-18, another cytokine processed by the NLRP3 inflammasome, is elevated in synovial fluid and serum of patients with OA, and has been proven to decrease type II collagen and aggrecan expression, disrupt autophagy and induce apoptosis in chondrocytes ( 230 , 231 ). A recent work shows that inhibition of the mTOR pathway after IL-18 treatment has protective effects in chondrocytes both in vitro and in vivo ( 232 ). Data suggest that IL-1β and IL-18 are mainly produced in the damaged synovium rather than cartilage ( 233 ).…”