Abstract
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.
Highlights
More than half a century ago, Gross and Lapière discovered collagenase-1, the first matrix metalloproteinase (MMP) [1]
In contrast to the collagenases MMP-1, MMP-8 and MMP-13, which are the main effectors of type I collagen degradation during wound repair, MMP-3 is incapable of cleaving native type I collagen
MMP-3 mRNA and protein were undetectable in the skin of MMP-3-deficient mice (KO)
Summary
More than half a century ago, Gross and Lapière discovered collagenase-1, the first matrix metalloproteinase (MMP) [1]. Apart from cleaving extracellular matrix proteins, e.g., E-cadherin, laminins and type IV collagen, MMP-3 activates cytokines, growth factors [3,4] and other MMP members, e.g., the collagenases MMP-1, MMP-8 and MMP-13 and gelatinase B (MMP-9) [3]. In contrast to the collagenases MMP-1, MMP-8 and MMP-13, which are the main effectors of type I collagen degradation during wound repair, MMP-3 is incapable of cleaving native type I collagen. Human skin explant cultures challenged with TNF-α reacted with a concomitant and increased MMP-1, MMP-3 and collagen degradation. In this human model, we hypothesized that the increased collagen degradation was due to the activation of the collagenase MMP-1 by MMP-3 [23]
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