Advanced glycation end products promote intervertebral disc degeneration by transactivation of matrix metallopeptidase genes

Objective: Examine the mechanism by which advanced glycation end products (AGEs) induce intervertebral disc degeneration (IDD) in C57BL/6J mice. Methods: Matrix metallopeptidase (MMP) gene mRNA levels were assessed using RT-qPCR. Immunoprecipitation and co-immunoprecipitation were performed to identify the transcriptional complex regulating MMP expression due to AGEs. The preventive effects of inhibitors targeting this complex were tested in mice on high AGE diets. Results: IDD and AGE accumulation were evident in mice on high -AGE diets (HAGEs), persisting across dietary shifts but absent in mice exclusively on low-AGE diets. Molecularly, HAGEs activated p21-activated kinase 1 (PAK1), prompting peroxisome proliferator-activated receptor gamma coactivator-related protein 1 (PPRC1) phosphorylation. Ubiquitin-specific protease 12 (USP12) interacted with the phosphorylated PPRC1 (pPPRC1), safeguarding it from proteasomal degradation. This pPPRC1, in collaboration with two histone acetyltransferases p300/CREB-binding protein (CBP) and a transcription factor activator protein 1(AP1), enhanced the expression of 12 MMP genes (MMP1a/1b/3/7/9/10/12/13/16/19/23/28). In vitro AGE exposure on nucleus pulposus and annulus fibrosus cells replicated this gene activation pattern, driven by the PAK1/ pPPRC1-p300/CBP-AP1 pathway. The application of PAK1, p300, and AP1 inhibitors reduced pPPRC1-p30 0/ CBP-AP1 binding to MMP promoters, diminishing their expression. These inhibitors effectively thwarted IDD in HAGE mice. Conclusion: Our results revealed that HAGEs instigate IDD via the PAK1/pPPRC1-p300/CBP-AP1 signaling pathway. This insight can guide therapeutic strategies to slow IDD progression in prediabetic/diabetic patients. (c) 2023 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.