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

Tekari, Adel; Marazza, Alessandro; Crump, Katherine; Bermudez-Lekerika, Paola; Gantenbein, Benjamin (2022). Inhibition of the extracellular signal-regulated kinase pathway reduces the inflammatory component in nucleus pulposus cells. (In Press). Journal of orthopaedic research Wiley 10.1002/jor.25273

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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-α 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Orthopaedic, Plastic and Hand Surgery (DOPH) > Clinic of Orthopaedic Surgery
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Crump, Katherine Briana; Bermudez, Paola and Gantenbein, Benjamin

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

0736-0266

Publisher:

Wiley

Language:

English

Submitter:

Benjamin Gantenbein

Date Deposited:

22 Feb 2022 17:49

Last Modified:

20 Mar 2022 17:54

Publisher DOI:

10.1002/jor.25273

PubMed ID:

35106811

Uncontrolled Keywords:

ERK TNF-α arthrosis intervertebral disc nucleus pulposus

BORIS DOI:

10.48350/165228

URI:

https://boris.unibe.ch/id/eprint/165228

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