Glucose-stimulated PGC-1α couples with CBP and Runx2 to mediate intervertebral disc degeneration through transactivation of ADAMTS4/5 in diet-induced obesity mice

被引：12

作者：

Tseng, Changchun ^{[1
]}

Han, Yingchao ^{[1
]}

Lv, Zhendong ^{[1
]}

Song, Qingxin ^{[1
]}

Wang, Kun ^{[1
]}

Shen, Hongxing ^{[1
,2
]}

Chen, Zhi ^{[1
,2
]}

机构：

[1] Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Spine Surg, Shanghai, Peoples R China

[2] 160 Pujian Rd, Shanghai 200127, Peoples R China

来源：

BONE | 2023年 / 167卷

关键词：

Intervertebral disc degeneration; ADAMTS; PGC-1; Runx2; Diabetic mice; EXPRESSION; ADAMTSS; MMPS; BETA;

D O I：

10.1016/j.bone.2022.116617

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Emerging evidence suggests that type 2 diabetes mellitus (T2DM) is associated with the pathogenesis of inter-vertebral disc degeneration (IDD). However, it is still unclear how T2DM contributes to IDD. Herein, we observed the accumulation of blood glucose and degenerative lumbar discs in mice fed a high-fat diet. Detection of differentially expressed genes in degenerative lumbar discs revealed that ADAMTS4 (A Disintegrin and Metal-loproteinase with Thrombospondin motifs) and ADAMTS5 genes were significantly increased. In vitro analyses demonstrated that Runt-Related Transcription Factor 2 (Runx2) recruited both PPARgamma Coactivator 1alpha (PGC-1 alpha) and CREB-Binding Protein (CBP) to transactivate the expression of ADAMTS4/5. Glucose stimulation could dose-dependently induce the accumulation of PGC-1 alpha and promoted the binding of the CBP-PGC-1 alpha-Runx2 complex to the promoters of ADAMTS4/5. Depletion of CBP-PGC-1 alpha-Runx2 complex members and treatment with either PGC-1 alpha inhibitor SR-18292 or CBP inhibitor EML425 in vitro could dramatically inhibit the glucose-induced expression of ADAMTS4/5. Administration of SR-18292 and EML425 in diabetic mice could prevent the degeneration of lumbar discs. Collectively, our results revealed a molecular mechanism by which the hyperglycemia-dependent CBP-PGC-1 alpha-Runx2 complex was required for the transactivation of ADAMTS4/5. The blockage of this complex in diabetic mice may help prevent IDD.

引用

页数：11