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Lookup NU author(s): Dr Jonathan Catterall,
Dr Severine Carrere,
Dr Beverley Degnan,
Dr William Shingleton,
Emeritus Professor Tim Cawston,
Emeritus Professor Drew Rowan
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Objective. To investigate the mechanism of interleukin-1 alpha (IL-1 alpha) and oncostatin M (OSM) synergistic regulation of matrix metalloproteinase 1 (MMP-1) in human chondrocytes. Methods. Using an immortalized human chondrocyte cell line (T/C28a4), we investigated regulation of the MMP-1 gene. Northern blotting and flow cytometric analysis were used to assess changes in receptor, MMP-1, and c-fos expression. Transient transfections using MMP-1 promoter/luciferase constructs, electrophoretic mobility shift assay, and site-directed mutagenesis were used to investigate MMP-1 promoter activation. Results. We found no alteration in the expression of receptors used by these cytokines after stimulation with IL-1 alpha /OSM. Using MMP-1 promoter/luciferase reporter constructs, we found that the proximal (-517/+63) region of the MMP-1 promoter was sufficient to support a synergistic activation. A role for activated signal transducers and activators of transcription (STAT-3) was demonstrated, although no binding of STAT-3 to the MMP-1 promoter was found. However, constitutive binding of activator protein 1 (AP-1) was detected, and changes in c-fos expression could modulate promoter activity. Conclusion. Since no changes in receptor expression were observed, receptor modulation cannot account for the IL-1 alpha /OSM synergy observed. Instead, the interplay of various intracellular signaling pathways is a more likely explanation. STAT activation is required, but STAT proteins do not interact directly with the MMP-1 promoter. We propose that activated STATs stimulate c-fos expression, and changes in expression of the AP-1 components regulate MMP-1 expression. We highlight a new mechanism for MMP-1 regulation in human chondrocytes that could provide potential new therapeutic targets.
Author(s): Catterall JB, Carrere S, Koshy PJT, Degnan BA, Shingleton WD, Brinckerhoff CE, Rutter J, Cawston TE, Rowan AD
Publication type: Article
Publication status: Published
Journal: Arthritis & Rheumatism
ISSN (print): 0004-3591
ISSN (electronic): 1529-0131
Publisher: John Wiley & Sons, Inc.
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