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Nucleic Acids Research, 2001, Vol. 29, No. 21 4361-4372
© 2001 Oxford University Press

IL-1 induces collagenase-3 (MMP-13) promoter activity in stably transfected chondrocytic cells: requirement for Runx-2 and activation by p38 MAPK and JNK pathways

John A. Mengshol1,2, Matthew P. Vincenti1 and Constance E. Brinckerhoff1,2,*

1Department of Medicine and 2Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03755, USA

Osteoarthritic chondrocytes secrete matrix metalloproteinase-13 (MMP-13) in response to interleukin-1 (IL-1), causing digestion of type II collagen in cartilage. Using chondrocytic cells, we previously determined that IL-1 induced a strong MMP-13 transcriptional response that requires p38 MAPK, JNK and the transcription factor NF-{kappa}B. Now, we have studied the tissue-specific transcriptional regulation of MMP-13. Constitutive expression of the transcription factor Runx-2 correlated with the ability of a cell type to express MMP-13 and was required for IL-1 induction; moreover, Runx-2 enhanced IL-1 induction of MMP-13 transcription by synergizing with the p38 MAPK signaling pathway. Transiently transfected MMP-13 promoters were not IL-1 inducible. However, –405 bp of stably integrated promoter was sufficient for 5- to 6-fold IL-1 induction of reporter activity and this integrated reporter required the same p38 MAPK pathway as the endogenous gene. Finally, mutation of the proximal Runx binding site and the proximal AP-1 site blunted the transcriptional response to IL-1, and double mutation synergistically decreased reporter activity. In summary, our  data suggest that the transcriptional MMP-13 response to IL-1 is controlled by the p38 pathway interacting at the MMP-13 promoter through the tissue-specific transcription factor Runx-2 and the ubiquitous AP-1 transcription factor.

* To whom correspondence should be addressed at: Department of Medicine, 505A Vail Building, Dartmouth Medical School, Hanover, NH 03755, USA. Tel: +1 603 650 1609; Fax: +1 603 650 1128; Email: constance.e.brinckerhoff{at}dartmouth.edu


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