Dysregulation of YAP by the Hippo pathway is involved in intervertebral disc degeneration, cell contact inhibition, and cell senescence
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Cong Zhang1, Feng Wang1, Zhiyang Xie1, Lu Chen1, Arjun Sinkemani1, Haomin Yu1, Kun Wang1, Lu Mao1 and Xiaotao Wu1
1Department of Spine Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
Xiaotao Wu, email: [email protected]
Keywords: Hippo pathway; YAP; LATS; intervertebral disc degeneration; nucleus pulposus
Abbreviations: YAP: yes-associated protein; LATS: large tumor suppressor kinases
Received: September 12, 2017 Accepted: December 04, 2017 Published: December 14, 2017
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.
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