Dysregulation of YAP by the Hippo pathway is involved in intervertebral disc degeneration, cell contact inhibition, and cell senescence.

Cong Zhang,Kun Wang,Arjun Sinkemani,Haomin Yu,Lu Chen,Xiaotao Wu,Lu Mao,Zhiyang Xie,Feng Wang

doi:10.18632/oncotarget.23299

Abstract

The Hippo pathway plays important roles in wound healing, tissue repair and regeneration, and in the treatment of degenerative diseases, by regulating cell proliferation and apoptosis in mammals. Intervertebral disc degeneration (IDD) is one of the major causes of low back pain, a widespread issue associated with a heavy economic burden. However, the mechanism underlying how the Hippo pathway regulates IDD is not well understood. Here, we demonstrate that the Hippo pathway is involved in natural IDD. Activation and dephosphorylation of yes-associated protein (YAP) were observed in younger rat discs, and decreased gradually with age. Surprisingly, Hippo pathway suppression was accompanied by overexpression of YAP, caused by acute disc injury, suggesting a limited ability for self-repair in IDD. We also demonstrated that YAP is inhibited by cell-to-cell contact via the Hippo pathway in vitro. Phosphorylation by large tumor suppressor kinases 1/2 (LATS1/2) led to cytoplasmic translocation and inactivation of YAP. YAP dephosphorylation was mainly localized in the nucleus and regulated by the Hippo pathway, whereas YAP dephosphorylation occurred in the cytoplasm and was associated with nucleus pulposus cell (NPC) senescence. Moreover, NPCs were transfected with shYAP and it accelerates the premature senescence of cells by interfered Hippo pathway through YAP. Therefore, our results indicate that the Hippo pathway plays an important role in maintaining the homeostasis of intervertebral discs and controlling NPC proliferation.

Highlights

Degeneration and injury of intervertebral discs result in alterations in mechanical and biological behaviors [1]
yes-associated protein (YAP) dephosphorylation was mainly localized in the nucleus and regulated by the Hippo pathway, whereas YAP dephosphorylation occurred in the cytoplasm and was associated with nucleus pulposus cell (NPC) senescence
These findings demonstrate that a 21 G needle puncture may cause more damage to discs, and that Intervertebral disc degeneration (IDD) reached a maximum value at 4 weeks after puncture

Summary

Introduction

Degeneration and injury of intervertebral discs result in alterations in mechanical and biological behaviors [1]. Intervertebral disc degeneration (IDD) induces neck and low back pain and is one of the most common causes of morbidity. It affects 70–85% of all individuals at some point in their lives and has enormous socioeconomic implications [2]. Treatment options for IDD include: 1) conservative methods using non-steroidal anti-inflammatory drugs (NSAIDs), physical therapy, rest, and lumbar muscle functional exercises; 2) surgical approaches consisting of disc arthroplasty, spinal fusion, and disc replacement; and 3) biomedical engineering techniques to attempt to retard the IDD process, including cell-based therapy, gene transfer, protein injection, and biomaterial implantation [3, 4]. Future studies aimed at understanding the mechanisms underlying IDD and developing novel therapies are highly warranted

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Conclusion