Inhibiting IL-1 signaling pathways to inhibit catabolic processes in disc degeneration

DANIELS, Jodie, BINCH, Abbie A. L. and LE MAITRE, Christine L. (2016). Inhibiting IL-1 signaling pathways to inhibit catabolic processes in disc degeneration. Journal of Orthopaedic Research. (In Press)

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Official URL: http://onlinelibrary.wiley.com/doi/10.1002/jor.233...
Link to published version:: 10.1002/jor.23363

Abstract

Intervertebral disc degeneration is characterized by an imbalance between catabolic and anabolic signaling, with an increase in catabolic cytokines particularly IL-1β, a key regulator of IVD degeneration. This study aimed to investigate intracellular signaling pathways activated by IL-1β, and GDF-5 in the degenerate IVD to identify potential new therapeutic targets. Human NP cells were cultured in alginate beads to regain in vivo phenotype prior to stimulation with IL-1β or GDF-5 for 30 min, a proteasome profiler array was initially utilized to screen activation status of 46 signaling proteins. Immunoflourescence was used to investigate activation of the NFκB pathway. Cell-based ELISAs were then deployed to confirm results for ERK1/2, p38 MAPK, c-jun, and IκB signaling. IHC was utilized to investigate native activation status within human IVD tissue between grades of degeneration. Finally, cells were stimulated with IL-1β in the absence or presence of p38 MAPK, c-jun, JNK, and NFκB inhibitors to investigate effects on MMP3, MMP13, IL-1β, IL-6, and IL-8 mRNA expression. This study demonstrated three key signaling pathways which were differentially activated by IL-1β but not GDF-5; namely p38 MAPK, c-jun, and NFκB. While ERK 1/2 was activated by both GDF-5 and IL-1. Immunohistochemistry demonstrated p38 MAPK, c-jun, and NFκB were activated during human IVD degeneration and inhibition of these pathways reduced or abrogated the catabolic effects of IL-1β, with inhibition of NFκB signaling demonstrating most widespread inhibition of IL-1β catabolic effects

Item Type: Article
Research Institute, Centre or Group: Biomolecular Sciences Research Centre
Identification Number: 10.1002/jor.23363
Depositing User: Ann Betterton
Date Deposited: 16 Aug 2016 12:44
Last Modified: 07 Dec 2016 19:17
URI: http://shura.shu.ac.uk/id/eprint/13222

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