Synergistic induction of matrix metalloproteinase 1 by interleukin-1? and oncostatin M in human chondrocytes involves signal transducer and activator of transcription and activator protein 1 transcription factors via a novel mechanism

Autor: Constance E. Brinckerhoff, B. A. Degnan, P. J. T. Koshy, W. D. Shingleton, Andrew D. Rowan, Joni L. Rutter, Jon B. Catterall, Tim E. Cawston, S. Carrère
Rok vydání: 2001
Předmět:
Zdroj: Arthritis & Rheumatism. 44:2296-2310
ISSN: 1529-0131
0004-3591
Popis: Objective To investigate the mechanism of interleukin-1α (IL-1α) 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-1α/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-1α/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.
Databáze: OpenAIRE
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