1. Academic Validation
  2. Glucagon-like peptide-1 receptor activation maintains extracellular matrix integrity by inhibiting the activity of mitogen-activated protein kinases and activator protein-1

Glucagon-like peptide-1 receptor activation maintains extracellular matrix integrity by inhibiting the activity of mitogen-activated protein kinases and activator protein-1

  • Free Radic Biol Med. 2021 Dec;177:247-259. doi: 10.1016/j.freeradbiomed.2021.10.034.
Yizhong Peng 1 Hui Lin 1 Shuo Tian 1 Sheng Liu 1 Jinye Li 1 Xiao Lv 1 Songfeng Chen 2 Lei Zhao 1 Feifei Pu 1 Xi Chen 1 Hongyang Shu 3 Xiangcheng Qing 4 Zengwu Shao 5
Affiliations

Affiliations

  • 1 Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 2 Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, 450052, China.
  • 3 Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China; Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan, 430000, China.
  • 4 Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. Electronic address: 353220817@qq.com.
  • 5 Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. Electronic address: szwpro@163.com.
Abstract

Disruption of the intervertebral disc extracellular matrix (ECM) is a hallmark of intervertebral disc degeneration (IDD), which is largely attributed to excessive oxidative stress. However, there is a lack of clinically feasible approaches to promote the reconstruction of the disc ECM. Glucagon-like peptide-1 (GLP-1), a safe polypeptide hormone adopted to treat type 2 diabetes mellitus, has shown great potential for relieving oxidative stress-related damage. To our knowledge, this is the first study to reveal that exenatide, a GLP-1 Receptor (GLP-1R) agonist, can upregulate disc ECM synthesis and attenuate oxidative stress-induced ECM degradation and IDD. Mechanistically, we found that exenatide inhibited the activation of mitogen-activated protein kinases (MAPK) signaling pathway and the formation of BATF/JUNs heterodimers (an index of activator protein-1 (AP-1) activity). The restoration of MAPK signaling activation reversed the protective effects of exenatide and enhanced downstream BATF/JUNs binding. BATF overexpression was also found to aggravate disc ECM damage, even in the presence of exenatide. In summary, exenatide is an effective agent that regulates ECM anabolic balance and restores disc degeneration by inhibiting MAPK activation and its downstream AP-1 activity. The present study provides a therapeutic rationale for activating the GLP-1 Receptor against IDD and establishes the important role of AP-1 activity in the pathogenesis of IDD.

Keywords

AP-1; BATF; Extracellular matrix; GLP-1R; Intervertebral disc degeneration; MAPK.

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