Toggle Main Menu Toggle Search

Open Access padlockePrints

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

Lookup NU author(s): Dr Jonathan Catterall, Dr Severine Carrere, Paul Koshy, Dr Beverley Degnan, Dr William Shingleton, Emeritus Professor Tim Cawston, Emeritus Professor Drew Rowan

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


Abstract

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.


Publication metadata

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

Year: 2001

Volume: 44

Issue: 10

Pages: 2296-2310

ISSN (print): 0004-3591

ISSN (electronic): 1529-0131

Publisher: John Wiley & Sons, Inc.

URL: http://dx.doi.org/10.1002/1529-0131(200110)44:10<2296::AID-ART392>3.0.CO;2-9

DOI: 10.1002/1529-0131(200110)44:10<2296::AID-ART392>3.0.CO;2-9


Altmetrics

Altmetrics provided by Altmetric


Actions

Find at Newcastle University icon    Link to this publication


Share