Browse by author
Lookup NU author(s): Chris Macdonald, Dr Adrian Falconer, Dr Chun Chan, Dr David Wilkinson, Andrew Skelton, Dr Louise Reynard, Dr Gary Litherland, Emeritus Professor Nick Europe-Finner, Emeritus Professor Drew Rowan
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2018 Macdonald et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Irreversible cartilage collagen breakdown by the collagenolytic matrix metalloproteinases (MMPs)-1 and MMP-13 represents a key event in pathologies associated with tissue destruction such as arthritis. Inflammation is closely associated with such pathology and occurs in both rheumatoid and osteoarthritis making it highly relevant to the prevailing tissue damage that characterises these diseases. The inflammation-induced activating protein-1 (AP-1) transcription factor is an important regulator of both MMP1 and MMP13 genes with interplay between signalling pathways contributing to their expression. Here, we have examined the regulation of MMP1 expression, and using in vivo chromatin immunoprecipitation analyses we have demonstrated that cFos bound to the AP-1 cis element within the proximal MMP1 promoter only when the gene was transcriptionally silent as previously observed for MMP13. Subsequent small interfering RNA-mediated silencing confirmed however, that cFos significantly contributes to MMP1 expression. In contrast, silencing of ATF3 (a prime MMP13 modulator) did not affect MMP1 expression whilst silencing of the Wnt-associated regulator cysteine- serine-rich nuclear protein-1 (CSRNP1) resulted in substantial repression of MMP1 but not MMP13. Furthermore, following an early transient peak in expression of CSRNP1 at the mRNA and protein levels similar to that seen for cFOS, CSRNP1 expression subsequently persisted unlike cFOS. Finally, DNA binding assays indicated that the binding of CSRNP1 to the AP-1 consensus-like sequences within the proximal promoter regions of MMP1 and MMP13 was preferentially selective for MMP1 whilst activating transcription factor 3 (ATF3) binding was exclusive to MMP13. These data further extend our understanding of the previously reported differential regulation of these MMP genes, and strongly indicate that although cFos modulates the expression of MMP1/13, downstream factors such as CSRNP1 and ATF3 ultimately serve as transcriptional regulators in the context of an inflammatory stimulus for these potent collagenolytic MMPs.
Author(s): Macdonald CD, Falconer AMD, Chan CM, Wilkinson DJ, Skelton A, Reynard L, Litherland GJ, Europe-Finner GN, Rowan AD
Publication type: Article
Publication status: Published
Journal: PLoS ONE
Year: 2018
Volume: 13
Issue: 11
Online publication date: 15/11/2018
Acceptance date: 27/10/2018
Date deposited: 28/11/2018
ISSN (electronic): 1932-6203
Publisher: Public Library of Science
URL: https://doi.org/10.1371/journal.pone.0207240
DOI: 10.1371/journal.pone.0207240
PubMed id: 30440036
Altmetrics provided by Altmetric
