Inhibition of the extracellular signal-regulated kinase pathway reduces the inflammatory component in nucleus pulposus cells

被引:5
|
作者
Tekari, Adel [1 ,2 ]
Marazza, Alessandro [1 ,3 ]
Crump, Katherine [1 ,4 ]
Bermudez-Lekerika, Paola [1 ,4 ]
Gantenbein, Benjamin [1 ,4 ]
机构
[1] Univ Bern, Med Fac, Dept BioMed Res DBMR, Tissue Engn Orthopaed & Mechanobiol Bone & Joint, Murtenstr 35, CH-3008 Bern, Switzerland
[2] Univ Sfax, Ctr Biotechnol Sfax, Lab Mol & Cellular Screening Proc, Sfax, Tunisia
[3] Temple Univ, Alzheimers Ctr Temple, Lewis Katz Sch Med, Philadelphia, PA 19122 USA
[4] Univ Bern, Bern Univ Hosp, Dept Orthopaed Surg & Traumatol, Inselspital, Bern, Switzerland
基金
欧盟地平线“2020”;
关键词
arthrosis; ERK; intervertebral disc; nucleus pulposus; TNF-alpha; NECROSIS-FACTOR-ALPHA; LOW-BACK-PAIN; ANNULUS FIBROSUS CELLS; TNF-ALPHA; SURGERY SYNDROME; GENE-EXPRESSION; LUMBAR SPINE; PROTEIN; HERNIATION; TISSUE;
D O I
10.1002/jor.25273
中图分类号
R826.8 [整形外科学]; R782.2 [口腔颌面部整形外科学]; R726.2 [小儿整形外科学]; R62 [整形外科学(修复外科学)];
学科分类号
摘要
Intervertebral disc (IVD) degeneration is a spinal disorder that triggers an inflammatory response and subsequent development of spinal pseudoarthrosis. The aim of the present study is to elucidate the role of the extracellular signal-regulated kinase (ERK) pathway in inflammation-induced IVD cells. Inflammatory human nucleus pulposus (NP) cells (NPCs) were induced using tumor necrosis factor-alpha and the ERK pathway was blocked using a selective molecule-based inhibitor U0126. Gene expression of catabolic and anabolic markers, proinflammatory, and NPCs markers was investigated. The enzymatic activity of matrix metalloproteinases (MMP)2/MMP9 was determined by gelatin zymography and nitrite production was assessed by Griess reaction. The NPC metabolic activity and viability were assessed using resazurin sodium-salt and live/dead assays, and subsequently, the specificity of U0126 on ERK1/2 signaling was determined. The catabolic enzyme MMP3 (p = 0.0001) and proinflammatory cytokine interleukin 6 (p = 0.036) were downregulated by U0126 in NPCs under inflammatory conditions. A significant increase of the cytokeratin 19 (p = 0.0031) was observed, suggesting a partial and possible recovery of the NP phenotype. U0126 does not seem to have an effect on prostaglandin production, aggrecanases, or other anabolic genes. We confirmed that U0126 selectively blocks the ERK phosphorylation and only affects the cell metabolic activity without the reduction of viable cells. Inhibition of ERK signaling downregulates important metalloproteinases and proinflammatory cytokines, and upregulates some NP markers, suggesting its potential to treat IVD degeneration.
引用
收藏
页码:2362 / 2371
页数:10
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