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Matrix Metalloproteinase-3 is Key Effector of TNF-α-Induced Collagen Degradation in Skin

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  • Ursula Mirastschijski
  • Blaž Lupše
  • Kathrin Maedler
  • Bhavishya Sarma
  • Arlo Radtke
  • Gazanfer Belge
  • Martina Dorsch
  • Dirk Wedekind
  • Lisa J McCawley
  • Gabriele Boehm
  • Ulrich Zier
  • Kazuhiro Yamamoto
  • Sørge Kelm
  • Magnus S Ågren
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Inflammatory processes in the skin augment collagen degradation due to the up-regulation of matrix metalloproteinases (MMPs). The aim of the present project was to study the specific impact of MMP-3 on collagen loss in skin and its interplay with the collagenase MMP-13 under inflammatory conditions mimicked by the addition of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). Skin explants from MMP-3 knock-out (KO) mice or from transgenic (TG) mice overexpressing MMP-3 in the skin and their respective wild-type counterparts (WT and WTT) were incubated ex vivo for eight days. The rate of collagen degradation, measured by released hydroxyproline, was reduced (p < 0.001) in KO skin explants compared to WT control skin but did not differ (p = 0.47) between TG and WTT skin. Treatment with the MMP inhibitor GM6001 reduced hydroxyproline media levels from WT, WTT and TG but not from KO skin explants. TNF-α increased collagen degradation in the WT group (p = 0.0001) only. More of the active form of MMP-13 was observed in the three MMP-3 expressing groups (co-incubation with receptor-associated protein stabilized MMP-13 subforms and enhanced detection in the media). In summary, the innate level of MMP-3 seems responsible for the accelerated loss of cutaneous collagen under inflammatory conditions, possibly via MMP-13 in mice.

Original languageEnglish
Article number5234
JournalInternational Journal of Molecular Sciences
Volume20
Issue number20
ISSN1661-6596
DOIs
Publication statusPublished - 1 Oct 2019

    Research areas

  • Cytokines, Extracellular matrix, Inflammation, Interstitial collagens, Proteinases

ID: 58656811