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Cited by 68Wound Healing and TreatmentsProtease and Inhibitor MechanismsPineapple and bromelain studies

The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.

Expression and Activation of Matrix Metalloproteinases in Wounds: Modulation by the Tripeptide–Copper Complex Glycyl-L-Histidyl-L-Lysine-Cu2+

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Siméon, Alain, Monier, Frédérique, Emonard, Hervé, Gillery, Philippe, Hornebeck, William, Maquart, François-Xavier, Birembaut, Philippe·1999·Journal of Investigative Dermatology
DOI 10.1046/j.1523-1747.1999.00606.x
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Abstract

We investigated the expression and activation of matrix metalloproteinases in a model of experimental wounds in rats, and their modulation by glycyl-L-histidyl-L-lysine-Cu(II), a potent activator of wound repair. Wound chambers were inserted under the skin of Sprague-Dawley rats and received serial injections of either 2 mg glycyl-L-histidyl-L-lysine-Cu(II) or the same volume of saline. The wound fluid and the neosynthetized connective tissue deposited in the chambers were collected and analyzed for matrix metalloproteinase expression and/or activity. Interstitial collagenase increased progressively in the wound fluid throughout the experiment. Glycyl-L-histidyl-L-lysine-Cu(II) treatment did not alter its activity. Matrix metalloproteinase-9 (gelatinase B) and matrix metalloproteinase-2 (gelatinase A) were the two main gelatinolytic activities expressed during the healing process. Pro-matrix metalloproteinase (pro-form of matrix metalloproteinase)-9 was strongly expressed during the early stages of wound healing (day 3). In the wound fluid, it decreased rapidly and disappeared after day 18, whereas in the wound tissue, matrix metalloproteinase-9 expression persisted in the glycyl-L-histidyl-L-lysine-Cu(II) injected chamber until day 22. Pro-matrix metalloproteinase-2 was expressed at low levels at the beginning of the healing process, increased progressively until day 7, then decreased until day 18. Activated matrix metalloproteinase-2 was present in wound fluid and wound tissue. It increased until day 12, then decreased progressively. Glycyl-L-histidyl-L-lysine-Cu(II) injections increased pro-matrix metalloproteinase-2 and activated matrix metalloproteinase-2 during the later stages of healing (days 18 and/or 22). These results demonstrate that various types of matrix metalloproteinases are selectively expressed or activated at the various periods of wound healing. Glycyl-L-histidyl-L-lysine-Cu(II) is able to modulate their expression and might significantly alter wound remodeling.

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Crossref · 10.1046/j.1523-1747.1999.00606.x

Cites

49 of 49 references verified0 citation errors · 0 not checkable

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  • GHK-Cu can serve as a natural copper supplement for connective tissue synthesis.

    “Since copper is an important trace element that plays a key factor in the production of collagen and elastin, GHK-Cu can be a natural supplement for copper in the connective tissue synthesis [10–11].”

    From The potential of GHK as an anti-aging peptide (2020) · cites this paper as [11]

    The Abstract says GHK binds copper to form GHK-Cu, and the wound-chamber results report increased collagen and extracellular-matrix deposition after GHK-Cu injection. The paper does not establish that GHK-Cu acts as a copper supplement for connective-tissue synthesis or address copper’s role in elastin production. Page numbers are unavailable in our copy. (LLM, conf=0.86)

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  • Copper is an important trace element in the production of collagen and elastin.

    “Since copper is an important trace element that plays a key factor in the production of collagen and elastin, GHK-Cu can be a natural supplement for copper in the connective tissue synthesis [10–11].”

    From The potential of GHK as an anti-aging peptide (2020) · cites this paper as [11]

    The Results section ('GHK-Cu increases extracellular matrix deposition in wound chambers'; page unavailable) reports increased collagen in wounds treated with the copper-containing complex GHK-Cu. It does not establish that copper alone is an important trace element for collagen production, and the passages found do not address elastin production (searched: 'elastin' and 'elastin synthesis copper connective tissue'). (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • GHK modulates activity of key metalloproteinases and anti-proteases, suggesting a general regulatory effect on protein breakdown in skin.

    “It also modulates activity of key metalloproteinases, which are enzymes that facilitate breakdown of proteins of extracellular matrix, as well as activity of anti-proteases. This suggests a general regulatory effect on protein breakdown in skin, helping to prevent both buildup of damaged proteins and excessive proteolysis [10,11].”

    From Regenerative and Protective Actions of the GHK-Cu Peptide in the Light of the New Gene Data (2018) · cites this paper as [10]

    The Discussion (page not available) reports increased proMMP-2 expression and activation in GHK-Cu-treated rat wounds, supporting modulation of a matrix metalloproteinase. It mentions the inhibitor TIMP-2 but does not show that GHK-Cu modulates anti-protease activity or prevents excessive proteolysis. The proposed general effect on protein breakdown in skin extends beyond the rat-wound findings. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • GHK-Cu regulated skin remodeling process in rats by modulating activity of different metalloproteinases.

    “In 1999, Maquart and co-authors demonstrated for the first time that GHK-Cu regulated skin remodeling process in rats by modulating activity of different metalloproteinases -enzymes that facilitate breakdown of proteins of extracellular matrix [7].”

    From Modulation of Gene Expression in Human Breast Cancer MCF7 and Prostate Cancer PC3 Cells by the Human Copper-Binding Peptide GHK-Cu (2021) · cites this paper as [7]

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Citations

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Research works printed but not linked: 6

  1. Downey, 1985, Acceleration of wound healing using glycyl-histidyl-lysine-Cu2+, Surg Forum, 48, 573
  2. Fish, 1991, Evaluation of glycyl-L-histidyl-L-lyusine-copper complex in acute wound healing. Effects in post Mohs/sugery wounds, Wounds, 3, 171
  3. Grosse, 1980, Experimental influence of the pharmacological agents on the regeneration of nervous tissue, In Vitro. Folia Morphol (Warsaw), 28, 345
  4. Lowry, 1951, Protein measurement with phenol-Folin reagent, J Biol Chem, 257, 5333
  5. Massey, 1992, The effects of glycyl-L-histidyl-L-lysine copper chelate on the healing of diabetic ulcers: a pilot study, Wounds, 4, 21
  6. Pickart, 1973, Tripeptide in human serum which prolongs survival of normal liver cells and stimulates the growth of hepatoma cells, Nature New Biol, 243, 85

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Metadata

Authors
Siméon, A., Monier, F., Emonard, H., Gillery, P., Hornebeck, W., Maquart, F.-X., & Birembaut, P.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Inserm (FR)
Corresponding author
Maquart, François-Xavier
ORCID
Venue
Journal of Investigative Dermatology
Publisher
Elsevier BV
Published
1999-06
Volume
112
Issue
6
Pages
957-964
ISSN
0022-202X (ISSN-L)
DOI
10.1046/j.1523-1747.1999.00606.x
OpenAlex
W1988686189
Semantic Scholar
bb3e580ea96165e17d4e223f8259c161c0127c3d
Cited by
68
References
49
Citations by year
2026: 3 · 2025: 4 · 2024: 2 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 6 · 2019: 2 · 2018: 4 · 2017: 1 · 2016: 7 · 2015: 4 · 2014: 3 · 2013: 2 · 2012: 1
FWCI
1.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Investigative Dermatology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Centre National de la Recherche Scientifique
  • Université de Reims Champagne-Ardenne
Topics
  • Health Sciences › Medicine › Surgery › Wound Healing and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pineapple and bromelain studies
Keywords
matrix metalloproteinases, wound healing, MMP-9, MMP-2, MMP-1, proMMP-2, MMP-9 activation, wound remodeling, gelatinase activity, wound fluid
MeSH terms
Animals, Enzyme Activation, Extracellular Matrix, Exudates and Transudates, Male, Metalloendopeptidases, Oligopeptides, Protein Precursors, RNA, Messenger, Wound Healing, Wounds and Injuries, Blotting, Northern, Rats, Sprague-Dawley, Collagenases, Gelatinases, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Rats

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