The tripeptide-copper complex glycyl-L-histidyl-L- lysine-Cu2+ stimulates matrix metalloproteinase-2 expression by fibroblast cultures
Abstract
Glycyl-histidyl-lysine-Cu2+ (GHK-Cu) is a tripeptide-copper complex known to be a potent wound healing agent. We previously showed its ability to stimulate in vitro and in vivo the synthesis of extracellular matrix components. The aim of this study was to determine the effects of GHK-Cu on MMP-2 synthesis by dermal fibroblasts in culture. We showed that GHK-Cu increased MMP-2 levels in conditioned media of cultured fibroblasts. This effect was reproduced by copper ions but not by the tripeptide GHK alone. This stimulation was accompanied by an increase of MMP-2 mRNA level. We also showed that GHK-Cu increased the secretion of the tissue inhibitors of metalloproteinases, TIMP-1 and TIMP-2. Taken together, our results underline that GHK-Cu is not only an activator of connective tissue production but also of the remodeling of the extracellular matrix. It is able to modulate MMP expression by acting directly on wound fibroblasts.
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Copper ions act as cofactors for enzymes involved in wound healing, such as elastases and metalloproteinases, facilitating autolysis of necrotic tissue.
“Additionally, copper ions act as cofactors for enzymes involved in wound healing, such as elastases and metalloproteinases. These enzymes facilitate the autolysis of necrotic tissue, contributing to copper dressings’ potent debridement effect.”
From The Journey of Copper-Impregnated Dressings in Wound Healing: From a Medical Hypothesis to Clinical Practice (2025) · cites this paper as [35]
The copper-binding activity of GHK is essential for its wound healing and skin remodeling effects.
“Since only GHK-Cu, but not GHK, exhibited those properties, it was concluded that the copper-binding activity of GHK is essential for its wound healing and skin remodeling effects [26].”
From GHK-Cu may Prevent Oxidative Stress in Skin by Regulating Copper and Modifying Expression of Numerous Antioxidant Genes (2015) · cites this paper as [26]
GHK modulates activity of different matrix metalloproteinases and stimulates anti-proteases, maintaining balance between matrix breakdown and synthesis.
“Next, it was shown that GHK not only modulates activity of different matrix metalloproteinases, but also stimulates anti-proteases, maintaining balance between matrix breakdown and synthesis [8].”
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 [8]
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- Authors
- Siméon, A., Emonard, H., Hornebeck, W., & Maquart, F.-X.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Maquart, François-Xavier
- Venue
- Life Sciences
- Publisher
- Elsevier BV
- Published
- 2000-09
- Volume
- 67
- Issue
- 18
- Pages
- 2257-2265
- ISSN
- 0024-3205 (ISSN-L)
- OpenAlex
- W2027981213
- Cited by
- 118
- References
- 0
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 3 · 2023: 10 · 2022: 5 · 2021: 3 · 2020: 7 · 2019: 3 · 2018: 3 · 2017: 3 · 2016: 8 · 2015: 12 · 2014: 4 · 2013: 3 · 2012: 3
- FWCI
- 0.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Life Sciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Centre National de la Recherche Scientifique
- Topics
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- GHK-Cu, MMP-2, dermal fibroblasts, copper ions, tissue inhibitors of metalloproteinases, TIMP-1, TIMP-2, extracellular matrix remodeling, wound healing, MMP-2 mRNA expression
- MeSH terms
- Animals, Cells, Cultured, Copper, Dose-Response Relationship, Drug, Enzyme Precursors, Fibroblasts, Growth Substances, Oligopeptides, Phosphoprotein Phosphatases, Tissue Inhibitor of Metalloproteinase-1, Tissue Inhibitor of Metalloproteinase-2, Matrix Metalloproteinase 2, Rats
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