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.
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DOI：
10.1016/j.freeradbiomed.2021.10.034
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发表时间：
2021-10
影响因子：
7.4
通讯作者：
Yizhong Peng;Hui Lin;Shuo Tian;Sheng Liu;Jinye Li;Xiao Lv;Songfeng Chen;Lei Zhao;Feifei Pu-Feif
中科院分区：
文献类型：
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作者：
Yizhong Peng;Hui Lin;Shuo Tian;Sheng Liu;Jinye Li;Xiao Lv;Songfeng Chen;Lei Zhao;Feifei Pu-Feif
椎间盘细胞外基质（ECM）的破坏是椎间盘退变（IDD）的一个标志，这主要归因于过度的氧化应激。然而，临床上缺乏可行的方法来促进椎间盘ECM的重建。胰高血糖素样肽-1 （Glucagon-like peptide-1, GLP-1）是一种用于治疗2型糖尿病的安全多肽激素，具有缓解氧化应激相关损伤的巨大潜力。据我们所知，这项研究首次揭示了艾塞那肽，一种GLP-1受体（GLP-1R）激动剂，可以上调椎间盘ECM的合成，并减轻氧化应激诱导的ECM降解和IDD。在机制上，我们发现艾塞那肽抑制了丝裂原活化蛋白激酶（MAPK）信号通路的激活和BATF/JUNs异源二聚体的形成（激活蛋白1 （AP-1）活性的指标）。MAPK信号激活的恢复逆转了艾塞那肽的保护作用，并增强了下游BATF/JUNs的结合。即使在艾塞那肽存在的情况下，也发现BATF过表达加重了椎间盘ECM损伤。综上所述，艾塞那肽是一种通过抑制MAPK激活及其下游AP-1活性来调节ECM合成代谢平衡和恢复椎间盘退变的有效药物。本研究为激活GLP-1受体对抗IDD提供了治疗依据，并确立了AP-1活性在IDD发病机制中的重要作用。
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.