Hyaluronan oligosaccharides induce matrix metalloproteinase 13 via transcriptional activation of NFκB and p38 MAP kinase in articular chondrocytes

被引:87
作者
Ohno, Shigeru [1 ]
Im, Hee-Jeong [1 ]
Knudson, Cheryl B. [1 ]
Knudson, Warren [1 ]
机构
[1] Rush Univ, Rush Med Coll, Med Ctr, Dept Biochem, Chicago, IL 60612 USA
关键词
D O I
10.1074/jbc.M602750200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 NF kappa B by hyaluronan oligosaccharides. NF kappa B activation was also documented in C-28/I2 immortalized human chondrocytes by luciferase promoter assays and phosphorylation of IKK-alpha/beta. The link between activation of NF kappa B and MMP-13 induction by HA oligosaccharides was further confirmed through the use of the NF kappa B 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 NF kappa B and p38 MAP kinase.
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收藏
页码:17952 / 17960
页数:9
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