IL‐6/YAP1/β‐catenin signaling is involved in intervertebral disc degeneration

Abstract

Yes‐associated protein 1 (YAP1) is a transcriptional coactivator and negative regulator of the Hippo pathway. It regulates diverse cellular processes, such as cell proliferation, contact inhibition, and tissue size. However, the role of YAP1 in intervertebral disc degeneration (IDD) remains elusive. Here, we demonstrated that YAP1 was activated by Interleukin 6 (IL‐6) through tyrosine phosphorylation in nucleus pulposus cells (NP cells). Overexpression of YAP1 decreased Sox‐9, Col‐II, aggrecan expression, whereas increased matrix metalloproteinases 13 level. In contrast, knockdown of YAP1 by small interfering RNA (siRNA) showed opposite effects and rescued IL‐6 induced NP cells degeneration. In addition, western blot showed that IL‐6 treatment increased YAP1 and β‐catenin protein level; co‐immunoprecipitation (Co‐IP) and immunofluorescence analysis showed that IL‐6 enhanced YAP1 and β‐catenin interaction and nuclear accumulation. Knockdown of β‐catenin by siRNA blocked IL‐6 treatment or YAP1 overexpression induced degeneration. Moreover, we found that verteporfin, a specific inhibitor of YAP1, effectively alleviated IDD development in rat disks. Taken together, our findings indicated that YAP1 plays an important role in IDD, and β‐catenin is essential for IL‐6/YAP1 signaling.

Gene polymorphisms and expression levels of interleukin-6 and interleukin-10 in lumbar disc disease: a meta-analysis and immunohistochemical study

“…IL-6 rs1800795 and rs1800797 polymorphisms, located within regulatory regions, could be part of RNAbinding protein site and could be involved in RNAbinding which is protein-mediated. Previous studies showed that IL-6 significantly induced disc degeneration by activating STAT3 and β-catenin signaling pathways [30,34]. It seems to indicate that IL-6 might act synergistically with other genetic factors contributing to the risk of disc degeneration.…”

Fibronectin Fragments and Inflammation During Canine Intervertebral Disc Disease

“…One study in dogs showed an upregulation in the gene expression of IL-8 and downregulation in the gene expression of IL-6 during IVDD (11). Increased levels of IL-6 and IL-8 in IVD in humans correlate with degeneration and inflammation within the IVD (36,(43)(44)(45)(46). Aside from its catabolic effects on NP cells, IL-6 is also involved in the development of pain during the course of IVDD (47).…”

The emerging role of Hippo signaling in neurodegeneration

“…Inside the nucleus, YAP/TAZ has been reported to act as a transcriptional coactivator for a multitude of proteins. YAP/TAZ interacts with additional DNA‐binding coactivators like TEADs, tumor protein p73, SMADs, FOXO proteins, T‐box transcription factor 5, RUNT‐related transcription factors (RUNX1, 2), and some other factors to regulate a diverse range of target gene expressions and thus diverse cellular responses (Boopathy & Hong, ; Chen et al, ; Fallahi et al, ). TEAD is one of the most studied transcriptional regulators that associate with YAP/TAZ.…”