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J. Biol. Chem., Vol. 281, Issue 34, 24124-24137, August 25, 2006

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Protein Kinase C Is Up-regulated in Osteoarthritic Cartilage and Is Required for Activation of NF-B by Tumor Necrosis Factor and Interleukin-1 in Articular Chondrocytes^*

Edward R. LaVallie¹, Priya S. Chockalingam^¶, Lisa A. Collins-Racie, Bethany A. Freeman, Cristin C. Keohan^¶, Michael Leitges^||, Andrew J. Dorner, Elisabeth A. Morris^¶, Manas K. Majumdar^¶, and Maya Arai

From the Departments of Biological Technologies and ^¶Women's Health and Musculoskeletal Biology, Wyeth Research, Cambridge, Massachusetts 02140-2325, ^||Hannover Medical School, Hannover 30625, Germany, and the Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts 02118-2526

Protein kinase C (PKC) is an intracellular serine/threonine protein kinase that has been implicated in the signaling pathways for certain inflammatory cytokines, including interleukin-1 (IL-1) and tumor necrosis factor (TNF-), in some cell types. A study of gene expression in articular chondrocytes from osteoarthritis (OA) patients revealed that PKC is transcriptionally up-regulated in human OA articular cartilage clinical samples. This finding led to the hypothesis that PKC may be an important signaling component of cytokine-mediated cartilage matrix destruction in articular chondrocytes, believed to be an underlying factor in the pathophysiology of OA. IL-1 treatment of chondrocytes in culture resulted in rapidly increased phosphorylation of PKC, implicating PKC activation in the signaling pathway. Chondrocyte cell-based assays were used to evaluate the contribution of PKC activity in NF-B activation and extracellular matrix degradation mediated by IL-1, TNF, or sphingomyelinase. In primary chondrocytes, IL-1 and TNF- caused an increase in NF-B activity resulting in induction of aggrecanase-1 and aggrecanase-2 expression, with consequent increased proteoglycan degradation. This effect was blocked by the pan-specific PKC inhibitors RO 31-8220 and bisindolylmaleimide I, partially blocked by Gö 6976, and was unaffected by the PKC-sparing inhibitor calphostin C. A cell-permeable PKC pseudosubstrate peptide inhibitor was capable of blocking TNFand IL-1-mediated NF-B activation and proteoglycan degradation in chondrocyte pellet cultures. In addition, overexpression of a dominant negative PKC protein effectively prevented cytokine-mediated NF-B activation in primary chondrocytes. These data implicate PKC as a necessary component of the IL-1 and TNF signaling pathways in chondrocytes that result in catabolic destruction of extracellular matrix proteins in osteoarthritic cartilage.

Received for publication, February 28, 2006 , and in revised form, June 8, 2006.

^* 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 To whom correspondence should be addressed: Dept. of Biological Technologies, Wyeth Research, 35 Cambridge Park Dr., Rm. Y1106, Cambridge, MA 02140. Tel.: 617-665-7068; Fax: 617-665-7240; E-mail: elavallie{at}wyeth.com.

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