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Extracellular Signal-Regulated Kinase Inhibition Modulates Rat Annulus Fibrosus Cell Response to Interleukin-1

Wei, Yuan, PhD; Zhi-hong, Wu, PhD; Gui-xing, Qiu, PhD; Bin, Yu, PhD; Jun, Chen, PhD; Yi-peng, Wang, PhD

doi: 10.1097/BRS.0b013e31829a6930
Basic Science
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Study Design. Rat annulus fibrosus (AF) cells were activated with interleukin-1 (IL-1) with or without extracellular signal-regulated kinase (ERK) inhibition. Factors associated with the anabolic/catabolic balance of the disc were determined.

Objective. To clarify the role of ERK pathway in AF cells response to IL-1.

Summary of Background Data. IL-1 plays an important role in intervertebral disc degeneration. ERK is an important inflammatory pathway that plays a crucial role in the expression of inflammatory and catabolic genes induced by IL-1 in chondrocytes. However, the role of the ERK pathway in AF cells response to IL-1 has not been fully investigated.

Methods. Rat AF cells in monolayer culture were exposed to IL-1, with or without ERK inhibition; ribonucleic acid was isolated for real time polymerase chain reaction analysis of gene expression, conditioned media analyzed for nitrite, prostaglandin E-2, and IL-6, Western blot was performed to detect the changes of protein expression.

Results. ERK specific inhibitor U0126 significantly inhibited IL-1–induced ERK activation. IL-1-dependent upregulation of iNOS, IL-6, Cox-2, (MMP)-3, and MMP-13 was significantly reduced by ERK inhibition. The decreased gene expression of collagen I, collagen II, collagen IX, and IGF-1 induced by IL-1 was also reversed by U0126. Gene expression of ADAMTS-4, ADAMTS-5, and TGF-b were not affected by IL-1 or ERK inhibition. IL-1 moderately upregulated aggrecan and TIMP-1 expression, ERK inhibition had no significant effect on aggrecan expression but decreased TIMP-1 expression in the presence of IL-1. ERK inhibition reversed the changes of protein expression of MMP-3, MMP-13, TIMP-1, aggrecan and collagen II induced by IL-1. IL-1–induced nitric oxide, prostaglandin E-2, and IL-6 accumulation were also reduced by ERK inhibition.

Conclusion. These results suggest that IL-1 induces an imbalance between anabolic and catabolic events in AF cells, ERK inhibition could provide some protection against the adverse effects of IL-1.

Level of Evidence: N/A

Interleukin-1 (IL-1) stimulation upregulated the expression of inflammatory and catabolic factors in rat annulus fibrosus cells. Extracellular signal-regulated kinase (ERK) inhibition blocked the inflammatory and catabolic effects of IL-1. The results suggest that ERK inhibition could provide some protection against the adverse effect of IL-1

All the authors were from the Department of orhopedic surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Address correspondence and reprint requests to Wang Yi-peng, PhD, Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Shuaifuyuan Hutong, 100730 Beijing, China; E-mail: YPWang@medmail.com

Acknowledgment date: November 6, 2012. Revision date: March 17, 2013. Acceptance date: May 3, 2013.

The manuscript submitted does not contain information about medical device(s)/drug(s).

National Natural Sciences Foundation of China grant (81130034) funds were received in support of this work.

No relevant financial activities outside the submitted work.

© 2013 by Lippincott Williams & Wilkins