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J. Biol. Chem., Vol. 281, Issue 26, 17952-17960, June 30, 2006

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Hyaluronan Oligosaccharides Induce Matrix Metalloproteinase 13 via Transcriptional Activation of NFB and p38 MAP Kinase in Articular Chondrocytes^*

From the Department of Biochemistry, Rush Medical College, Rush University Medical Center, Chicago, Illinois 60612

Hyaluronan exerts a variety of biological effects on cells including changes in cell migration, proliferation, and matrix metabolism. However, the signaling pathways associated with the action of hyaluronan on cells have not been clearly defined. In some cells, signaling is induced by the loss of cell-hyaluronan interactions. The goal of this study was to use hyaluronan oligosaccharides as a molecular tool to explore the effects of changes in cell-hyaluronan interactions and determine the underlying molecular events that become activated. In this study, hyaluronan oligosaccharides induced the loss of extracellular matrix proteoglycan and collagen from cultured slices of normal adult human articular cartilage. This loss was coincident with an increased expression of matrix metalloproteinase (MMP)-13. MMP-13 expression was also induced in articular chondrocytes by hyaluronan (HA) hexasaccharides but not by HA tetrasaccharides nor high molecular weight hyaluronan. MMP-13 promoter-reporter constructs in CD44-null COS-7 cells revealed that both CD44-dependent and CD44-independent events mediate the induction of MMP-13 by hyaluronan oligosaccharides. Electromobility gel shift assays demonstrated the activation of chondrocyte NFB by hyaluronan oligosaccharides. NFB activation was also documented in C-28/I2 immortalized human chondrocytes by luciferase promoter assays and phosphorylation of IKK-/. The link between activation of NFB and MMP-13 induction by HA oligosaccharides was further confirmed through the use of the NFB inhibitor helenalin. Inhibition of MAP kinases also demonstrated the involvement of p38 MAP kinase in the hyaluronan oligosaccharide induction of MMP-13. Our findings suggest that hyaluronan-CD44 interactions affect matrix metabolism via activation of NFB and p38 MAP kinase.

Received for publication, March 23, 2006 , and in revised form, April 24, 2006.

^* This work was supported in part by National Institutes of Health Grants RO1-AR43384, T32-AR07590, and P50-AR39239. 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 Biochemistry, Rush Medical College Rush University Medical Center, 1735 West Harrison St., Chicago, IL 60612. Tel.: 312-942-7837; Fax: 312-942-3053; E-mail: Warren_Knudson{at}rush.edu.

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