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A new redox-dependent mechanism of MMP-1 activity control comprising reduced low-molecular-weight thiols and oxidizing radicals

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Abstract

Matrix metalloproteinases (MMPs), a family of zinc-dependent proteinases, participate in remodeling and degradation of the extracellular matrix proteins. The activity of MMPs is thought to be predominately posttranslationally regulated via proteolytic activation of precursor zymogens or via their naturally occurring endogenous inhibitors. Here, using recombinant MMP-1, we investigated new redox-dependent mechanisms of proteinase activity regulation by low-molecular-weight thiols. We find that glutathione (GSH), cysteine, homocysteine, and N-acetylcysteine at physiological concentrations competitively reduce MMP-1 activity up to 75% with an efficiency of cysteine ≥ GSH > homocysteine > N-acetylcysteine. In contrast, S-derivatized thiols completely lack this inhibitory activity. Interestingly, the competitive GSH-mediated inhibition of MMP-1-activity can be fully reversed abrogated by oxidizing radicals like •NO2 or Trolox radicals, here generated by UVA irradiation of nitrite or Trolox, two relevant agents in human skin physiology. This redox-dependent reactivation of the inactive GSH–MMP-1-complex comprises GSH oxidation and is significantly inhibited in the presence of ascorbic acid, an effective •NO2 and Trolox radical scavenger. We here offer a new concept of redox-sensitive control of MMP-1 activity based on the inhibitory effect of reduced thiols and reactivation by a mechanism comprising derivatization or oxidation of the MMP-1-bound inhibitory-acting thiol.

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Abbreviations

MMP-1:

matrix metalloproteinase-1

GSH:

glutathione

GSSG:

oxidized glutathione

ECM:

extracellular matrix

TIMP:

tissue inhibitors of MMPs

•NO:

nitric oxide

•NO2:

nitrogen dioxide

ROS:

reactive oxygen species

RNS:

reactive nitrogen species

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Authors and Affiliations

  1. Institute of Biomedicine/Biochemistry, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, P.O. Box 63, 00014, Helsinki, Finland

    Sabine Koch

  2. Department of Immunobiology, Heinrich-Heine-University Düsseldorf, P.O. Box 101007, 40001, Düsseldorf, Germany

    Sabine Koch & Victoria Kolb-Bachofen

  3. Department of Plastic and Reconstructive Surgery, Hand Surgery, and Burn Center, Medical Faculty, RWTH Aachen University, Pauwelsstraβe 30, 52074, Aachen, Germany

    Christine M. Volkmar, Norbert Pallua & Christoph V. Suschek

  4. Institute of Organic Chemistry, University Duisburg-Essen, Universitätsstraße 5, 45117, Essen, Germany

    Hans-Gert Korth

  5. Institute of Physiological Chemistry, University Hospital Essen, Hufelandstraße 55, 45122, Essen, Germany

    Michael Kirsch

  6. Abteilung Bioinformatik, Institut für Biochemie, Emil-Fischer-Zentrum, Universität Erlangen-Nürnberg, Fahrstraβe 17, 91054, Erlangen, Germany

    Anselm H. C. Horn & Heinrich Sticht

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  1. Sabine Koch
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  2. Christine M. Volkmar
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  9. Christoph V. Suschek
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Correspondence to Christoph V. Suschek.

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Koch, S., Volkmar, C.M., Kolb-Bachofen, V. et al. A new redox-dependent mechanism of MMP-1 activity control comprising reduced low-molecular-weight thiols and oxidizing radicals. J Mol Med 87, 261–272 (2009). https://doi.org/10.1007/s00109-008-0420-5

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  • DOI: https://doi.org/10.1007/s00109-008-0420-5

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