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

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.