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Zhaoyang Guo,1,* Yuanye Ma,1,* Yaqing Wang,2 Hongfei Xiang,1 Shang-You Yang,3 Zhu Guo,1 Ronghuan Wang,1 Wujun Chen,4 Dongming Xing,4,5 Bohua Chen,1 Hao Tao,1 Xiaolin Wu1,4 1Department of Orthopedics, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 2Department of Nephrology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China; 3School of Medicine-Wichita, University of Kansas, Wichita, KS, USA; 4Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, People’s Republic of China; 5School of Life Sciences, Tsinghua University, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaolin Wu; Hao Tao, Department of Orthopedics, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China, Email fyqs01@qdu.edu.cn; taohaob2008@163.comBackground: It is well established that discogenic low back pain (DLBP) is often caused by the inflammatory response during intervertebral disc degeneration (IDD). However, it remains unclear how inflammatory mediators such as Interleukin-6 (IL-6) are involved in discogenic pain caused by degeneration and intervertebral disc (IVD) metabolism. The purpose of this study is to study the relationship between IL-6 and Transmembrane protein 100 (TMEM100), and to analyze the different metabolites and metabolic pathways in various rat intervertebral discs by metabonomics.Methods: We established a rat model of IDD-DLBP by disc punctures and PBS infusion to examine the rat pain behaviors. Intervertebral disc tissues were harvested for molecular biology experiments to explore the relationship between IL-6 and TMEM100. High-resolution mass spectrometry (HRMS) was performed for untargeted metabolomics, and nuclear magnetic resonance spectroscopy metabolomics (MRS) for differential metabolites and metabolic pathways.Results: The results showed a significant decrease in vonFrey test, hot plate test and acetone test (P < 0.05). The expression of IL-6 and TMEM100 in DLBP model was significantly higher than that in sham control group and IDD discs without PBS infusion group (P < 0.05). There were 15 major contributing metabolites identified in the DLBP intervertebral discs through metabolomic studies, involving 6 major metabolic pathways. The main differential metabolites included nitric oxide (NO), ammonia, and lactic acid as the metabolic endpoints; and the differential metabolic pathways included the glycine-serine-threonine (Gly-Ser-Thr), which is gradually weakened with the progression of inflammation.Conclusion: The change of TMEM100 expression mediated by il-6 is related to the Gly-Ser-Thr metabolic axis and plays an important role in the relief of discogenic pain.Keywords: metabolomics, DLBP, IDD, IL-6, TMEM100, inflammatory mediators |