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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 
 

Activation of the discoidin domain receptor 2 induces expression of matrix metalloproteinase 13 associated with osteoarthritis in mice.

Human genetic studies indicate that mutations in type IX and XI collagens result in early-onset osteoarthritis (OA) with a wide spectrum of osteochondrodysplasia. However, a convincing causal chain of events underlying the role of these collagen mutations in the pathogenesis of OA has not been elucidated. Here we show that the expression of a cell surface collagen receptor, discoidin domain receptor 2 (DDR2), is increased in chondrocytes of the articular cartilage of knee joints in mice that develop OA as a result of a heterozygous mutation in type XI collagen. At the same time point, 6 months, we also found increased expression and activity of matrix metalloproteinase 13 ( MMP-13) in the mutant mouse knee cartilage. The expression of both DDR2 and MMP-13 was increased in chondrocytes cultured on plates coated with native type II collagen but not on gelatin, and overexpression of DDR2, but not of a truncated form, was found to induce the expression of MMP-13 when chondrocytes were cultured on type II collagen but not on plastic. The DDR2- induced expression of MMP-13 appears to be specific, since we did not observe induction of MMP-1, MMP-3, MMP-8, ADAMTS-4, ADAMTS-5, and IL-1 transcripts in human chondrocytes or Mmp-3, Mmp-8, Adamts-4, Adamts-5, and Il-1 in mouse chondrocytes. Our data suggest that the defect in the cartilage matrix of mice that are heterozygous for a type XI collagen mutation (cho/+) permits activation and up-regulation of DDR2 in chondrocytes. This could be due to increased exposure of chondrocytes to type II collagen as a result of the decreased amount of type XI collagen in the mutant cartilage. The specific induction of MMP-13 by DDR2 in response to its cartilage-specific ligand, type II collagen, may contribute to cartilage damage in hereditary OA.[1]

References

  1. Activation of the discoidin domain receptor 2 induces expression of matrix metalloproteinase 13 associated with osteoarthritis in mice. Xu, L., Peng, H., Wu, D., Hu, K., Goldring, M.B., Olsen, B.R., Li, Y. J. Biol. Chem. (2005) [Pubmed]
 
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