The Sirt1/P53 Axis in Diabetic Intervertebral Disc Degeneration Pathogenesis and Therapeutics.

Zengjie Zhang,Chenggui Wang,Xiangyang Wang,Haiming Jin,Tianzhen Xu,Xiaolei Zhang,Naifeng Tian,Jiaoxiang Chen,Jialiang Lin,Gang Zheng,Tingting Chen,Weiyang Gao,Majid Nisar

doi:10.1155/2019/7959573

Abstract

Intervertebral disc degeneration (IDD) is one of the major causes of low back pain. Diabetes is a risk factor for IDD and may aggravate IDD in rats; however, the mechanism is poorly understood. Previously, we demonstrated that apoptosis and senescence were increased in diabetic nucleus pulposus (NP) tissues; in the current study, we found that hyperglycaemia may promote the incidence of apoptosis and senescence in NP cells in vitro. Meanwhile, the acetylation of P53, a master transcription factor of apoptosis and senescence, was also found increased in diabetic NP tissues in vivo as well as in hyperglycaemic NP cells in vitro. Sirt1 is an NAD+-dependent deacetylase, and we showed that the expression of Sirt1 was decreased in NP tissues, while hyperglycaemia could suppress the expression and activity of Sirt1 in NP cells. Furthermore, we demonstrated that butein may inhibit acetylation of P53 and protect NP cells against hyperglycaemia-induced apoptosis and senescence through Sirt1 activation, as the Sirt1 inhibitor Ex527 may counteract the protective effect of butein in hyperglycaemic NP cells. An in vivo study showed that butein could ameliorate the IDD process in diabetic rats, while Sirt1 was increased and acetyl-p53 was decreased in NP tissues in butein-treated rats. These results indicate that the Sirt1/P53 axis is involved in the pathogenesis of diabetic IDD and may serve as a therapeutic target for diabetic IDD.

Highlights

Low back pain is one of the most prevalent disorders and the leading cause of disability around the world [1, 2]
TUNEL assay results showed that the incidence of apoptosis was obviously increased in nucleus pulposus (NP) cells treated with 50 mM glucose for 24 and 48 h (Figures 1(c) and 1(d)) (p < 0 01)
Our results suggest that treatment with different concentrations of glucose for different durations can markedly promote apoptosis in NP cells

Summary

Introduction

Low back pain is one of the most prevalent disorders and the leading cause of disability around the world [1, 2]. Intervertebral disc degeneration (IDD) is widely known to contribute to low back pain [3]. Various factors including aberrant mechanical stress, inflammation, and genetic mutations have been proposed to contribute to the development of IDD [4,5,6,7]; the cellular and molecular mechanisms of IDD remain unclear, and effective treatments for IDD are still lacking. The intervertebral disc is an elegant structure composed of the nucleus pulposus (NP), annulus fibrosus (AF), and endplate cartilage (EPC) [8]. Dysfunction of the NP is considered the initiating factor for IDD [9, 10]

Methods

Results

Conclusion