c-Jun N-terminal kinase – c-Jun pathway transactivates Bim to promote osteoarthritis

Abstract

Osteoarthritis (OA) is a chronic degenerative joint disorder. Previous studies have shown abnormally increased apoptosis of chondrocytes in patients and animal models of OA. TNF-α and nitric oxide have been reported to induce chondrocyte ageing; however, the mechanism of chondrocyte apoptosis induced by IL-1β has remained unclear. The aim of this study is to identify the role of the c-Jun N-terminal kinase (JNK) - c-Jun pathway in regulating induction of Bim, and its implication in chondrocyte apoptosis. This study showed that Bim is upregulated in chondrocytes obtained from the articular cartilage of OA patients and in cultured mouse chondrocytes treated with IL-1β. Upregulation of Bim was found to be critical for chondrocyte apoptosis induced by IL-1β, as revealed by the genetic knockdown of Bim, wherein apoptosis was greatly reduced in the chondrocytes. Moreover, activation of the JNK-c-Jun pathway was observed under IL-1β treatment, as indicated by the increased expression levels of c-Jun protein. Suppression of the JNK-c-Jun pathway, using chemical inhibitors and RNA interference, inhibited the Bim upregulation induced by IL-1β. These findings suggest that the JNK-c-Jun pathway is involved in the upregulation of Bim during OA and that the JNK-c-Jun-Bim pathway is vital for chondrocyte apoptosis.

Autophagy inhibits chemotherapy-induced apoptosis through downregulating Bad and Bim in hepatocellular carcinoma cells

“…It is well known that autophagy is a proteolytic pathway, so how can this process downregulate the mRNA expression levels of Bad and Bim (Figure 2A)? Previous studies have shown that the transcriptional expression levels of Bad and Bim can be regulated by certain signaling pathways, such as those for JNK23 and TGF-β24. In addition, the relationship between JNK, TGF-β and autophagy has been widely reported2526; therefore, some regulatory factors in the JNK or TGF-β pathways may be degraded by autophagy, which would cause the transcriptional downregulation of Bad and Bim.…”

The Role of Inflammatory and Anti-Inflammatory Cytokines in the Pathogenesis of Osteoarthritis

“…A major role is attributed to ADAMTS-4, whose production is stimulated by both IL-1 β and TNF α , while ADAMTS-5 has no correlation with the influence of cytokines and is produced constitutively [33, 34]. Chondrocytes subjected to the effect of IL-1 β and TNF α also tend to age more rapidly and to induce apoptosis [35–37]. When analyzing the above information, one can observe the manifold effect of IL-1 β on cartilage by inhibiting its restoration possibility, intensifying its deterioration by enzymes and a direct adverse effect on chondrocytes.…”

“…Activated chondrocytes also produce MMP-1, MMP-3, MMP-13, and ADAMTS-4 [33, 90, 91]. As described earlier, there is an induction of chondrocyte death and a disorder in the migration of chondrogenic progenitor cells (CPCs), which strips the cartilage of any possibility of regeneration [35–37, 92]. A clear impact of TNF α and IL-1 β on reducing the efficiency of the respiratory chain was also observed, and hence the decrease in ATP produced within the mitochondria located in chondrocytes; additionally, there is a decrease in the potential of the mitochondrial membrane [93].…”

Differential Diagnosis of Osteoarthritis and Rheumatoid Arthritis by Bioinformatics Analysis

“…Immunohistochemicalstudies reveal that c-Jun proteins areupregulated in chondrocytes from the articular cartilage of OA patients [23] . Additionally, studies have shown that c-Jun regulates chondrocyte apoptosis during OA [24] .…”