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Protein Kinase C Isoforms ζ and Ɩ Mediate Collagenase Expression and Cartilage Destruction via STAT3- and ERK-dependent c-fos Induction

Lookup NU author(s): Dr Gary Litherland, Martina Elias, Dr Jonathan Catterall, Dr Matthew Barter, Matthew Farren, Dr Matthew Jefferson, Emeritus Professor Drew Rowan


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The protein kinase C (PKC) signaling pathway is a major regulator of cellular functions and is implicated in pathologies involving extracellular matrix remodeling. Inflammatory joint disease is characterized by excessive extracellular matrix catabolism, and here we assess the role of PKC in the induction of the collagenases, matrix metalloproteinase (MMP)-1 and MMP-13, in human chondrocytes by the potent cytokine stimulus interleukin-1 (IL-1) in combination with oncostatin M(OSM). IL-1 + OSM-stimulated collagenolysis and gelatinase activity were ameliorated by pharmacological PKC inhibition in bovine cartilage, as was collagenase gene induction in human chondrocytes. Small interfering RNA-mediated silencing of PKC gene expression showed that both novel (nPKC delta, nPKC eta) and atypical (aPKC zeta, aPKC iota) isoforms were involved in collagenase induction by IL-1. However, MMP1 and MMP13 induction by IL-1 + OSM was inhibited only by aPKC silencing, suggesting that only atypical isoforms play a significant role in complex inflammatory milieus. Silencing of either aPKC led to diminished IL-1 + OSM-dependent extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription (STAT) 3 phosphorylation, and c-fos expression. STAT3 gene silencing or ERK pathway inhibition also resulted in loss of IL-1 + OSM-stimulated c-fos and collagenase expression. Silencing of c-fos and c-jun expression was sufficient to abrogate IL-1 + OSM-stimulated collagenase gene induction, and overexpression of both c-fos and c-jun was sufficient to drive transcription from the MMP1 promoter in the absence of a stimulus. Our data identify atypical PKC isozymes as STAT and ERK activators that mediate c-fos and collagenase expression during IL-1 + OSM synergy in human chondrocytes. aPKCs may constitute potential therapeutic targets for inflammatory joint diseases involving increased collagenase expression.

Publication metadata

Author(s): Litherland GJ, Elias MS, Hui W, Macdonald CD, Catterall JB, Barter MJ, Farren MJ, Jefferson M, Rowan AD

Publication type: Article

Publication status: Published

Journal: Journal of Biological Chemistry

Year: 2010

Volume: 285

Issue: 29

Pages: 22414-22425

Print publication date: 12/05/2010

ISSN (print): 0021-9258

ISSN (electronic): 1083-351X

Publisher: American Society for Biochemistry and Molecular Biology, Inc.


DOI: 10.1074/jbc.M110.120121


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Funder referenceFunder name
Dunhill Medical Trust
UK National Institute of Health Research Biomedical Research Centre for Aging and Age-Related Disease
John G. W. Patterson Foundation
Nuffield Foundation
18726Arthritis Research UK