Cytokine-induced cysteine- serine-rich nuclear protein-1 (CSRNP1) selectively contributes to MMP1 expression in human chondrocytes

Christopher D. Macdonald, Adrian M.D. Falconer, Chun Ming Chan, David J. Wilkinson, Andrew Skelton, Louise Reynard, Gary J. Litherland, G. Nicholas Europe-Finner, Andrew D. Rowan

Research output: Contribution to journalArticle

1 Citation (Scopus)
3 Downloads (Pure)

Abstract

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.
Original languageEnglish
Article numbere0207240
Number of pages16
JournalPLoS ONE
Volume13
Issue number11
DOIs
Publication statusPublished - 15 Nov 2018
Externally publishedYes

Keywords

  • Protease activity
  • Cartilage, Articular
  • Osteoarthritis
  • Transcriptional Activation
  • Cytokines

Fingerprint Dive into the research topics of 'Cytokine-induced cysteine- serine-rich nuclear protein-1 (CSRNP1) selectively contributes to MMP1 expression in human chondrocytes'. Together they form a unique fingerprint.

  • Research Output

    • 1 Citations
    • 2 Article

    Protein kinase D3 modulates MMP1 and MMP13 expression in human chondrocytes

    Baker, J., Falconer, A., Wilkinson, D. J., Europe-Finner, G. N., Litherland, G. & Rowan, A. D., 13 Apr 2018, In : PLoS ONE. 13, 4, 19 p., e0195864.

    Research output: Contribution to journalArticle

    Open Access
  • 9 Citations (Scopus)

    Cytokine-Induced MMP13 Expression in Human Chondrocytes is dependent on Activating Transcription Factor 3 (ATF3) regulation

    Chan, C. M., Macdonald, C. D., Litherland, G., Wilkinson, D. J., Skelton, A., Europe-Finner, G. N. & Rowan, A. D., 12 Dec 2016, In : Journal of Biological Chemistry.

    Research output: Contribution to journalArticle

    Open Access
  • 16 Citations (Scopus)

    Cite this

    Macdonald, C. D., Falconer, A. M. D., Chan, C. M., Wilkinson, D. J., Skelton, A., Reynard, L., Litherland, G. J., Europe-Finner, G. N., & Rowan, A. D. (2018). Cytokine-induced cysteine- serine-rich nuclear protein-1 (CSRNP1) selectively contributes to MMP1 expression in human chondrocytes. PLoS ONE, 13(11), [e0207240]. https://doi.org/10.1371/journal.pone.0207240