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

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.

Automated summary

Emerging evidence suggests that type 2 diabetes mellitus (T2DM) is associated with inter-vertebral disc degeneration (IDD). However, the mechanism behind this association is still unclear. This study identified that the CBP-PGC-1 alpha-Runx2 complex is required for the activation of ADAMTS4/5 genes, and blocking this complex could prevent IDD in diabetic mice.