2. Academic Validation
  3. Advanced glycation end products promote intervertebral disc degeneration by transactivation of matrix metallopeptidase genes

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

  • Osteoarthritis Cartilage. 2023 Sep 15;S1063-4584(23)00918-4. doi: 10.1016/j.joca.2023.09.005.
Changchun Tseng 1,  Bin Chen 1,  Yingchao Han 1,  Kun Wang 1,  Qingxin Song 1,  Hongxing Shen 1,  Zhi Chen 2
Affiliations

Affiliations

  • 1 Department of Spine Surgery, Department of Orthopedics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 2 Department of Spine Surgery, Department of Orthopedics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: [email protected].
PMID: 37717904 DOI: 10.1016/j.joca.2023.09.005
Abstract

Objective: Examine the mechanism by which advanced glycation end products (AGEs) induce intervertebral disc (IVD) 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, persisting across dietary shifts but absent in mice exclusively on low-AGE diets. Molecularly, high-AGE diets activated p21-Activated Kinase 1 (PAK1), prompting PPRC1 (Peroxisome Proliferator-activated Receptor gamma coactivator-related protein 1) 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/CBP and a transcription factor AP1 (activator protein 1), 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-p300/CBP-AP1 binding to MMP promoters, diminishing their expression. These inhibitors effectively thwarted IDD in high-AGE diet mice.

Conclusion: Our results revealed that high-AGE diets 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.

Keywords

AP1; IVD degeneration; MMP; PAK1; PPRC1; advanced glycation end products.

Figures
Products