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J. Biol. Chem., Vol. 283, Issue 21, 14221-14229, May 23, 2008

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Synergistic Collagenase Expression and Cartilage Collagenolysis Are Phosphatidylinositol 3-Kinase/Akt Signaling-dependent^*

From the Cell Signalling, Injury, and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne NE2 4HH, United Kingdom

The phosphatidylinositol 3-kinase (PI3K) signaling pathway has emerged as a major regulator of cellular functions and has been implicated in several pathologies involving remodeling of extracellular matrix (ECM). The end stage of inflammatory joint diseases is characterized by excessive ECM catabolism, and in this study we assess the role of PI3K signaling in the induction of collagenolytic matrix metalloproteinases (MMPs) in human chondrocytes. We used the most potent cytokine stimulus reported to promote cartilage ECM catabolism, namely interleukin-1 (IL-1) in combination with oncostatin M (OSM). Both OSM and IL-6 (in the presence of its soluble receptor), but not IL-1 nor leukemia inhibitory factor, induced Akt phosphorylation in human chondrocytes. Inhibition of PI3K signaling using LY294002 blocked IL-1+OSM-mediated Akt phosphorylation, induction of MMP-1 and MMP-13, and cartilage collagenolysis. To further explore the role of downstream substrates within the PI3K pathway, complementary use of small molecule inhibitors and specific small interfering RNAs demonstrated that the PI3K subunit p110 and Akt1 were required for MMP-1 mRNA induction. MMP-13 induction was also reduced by loss of function of these molecules and by a lack of p110, 3-phosphoinositide-dependent kinase-1 or Akt3. We therefore propose that the activities of specific elements of the PI3K signaling pathway, including Akt, are necessary for the synergistic induction of MMP-1 and MMP-13 and the cartilage breakdown stimulated by IL-1+OSM. Our data provide new insight into the mechanism of synergy between IL-1 and OSM and highlight new therapeutic targets for inflammatory joint diseases that aim to repress the expression of collagenases.

Received for publication, December 12, 2007 , and in revised form, February 15, 2008.

^* This work was supported in part by the Arthritis Research Campaign, the Nuffield Foundation (Oliver Bird Fund), the Dunhill Medical Trust, and the JGWP Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Current address: IDS Ltd., Boldon Business Park, Boldon, Newcastle upon Tyne NE35 9PD, UK.

² To whom correspondence should be addressed: Cell Signalling, Injury, and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. Tel.: 44-191-222-8821; Fax: 44-191-222-5455; E-mail: a.d.rowan{at}ncl.ac.uk.

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