GHK-Cu Research: Collagen, Wound Models and Copper Binding
GHK-Cu is the copper(II) complex of GHK, a tripeptide of glycine, histidine and lysine (Gly-His-Lys). GHK was first reported in 1973 as a tripeptide in human serum with an effect on cultured liver cells (Pickart & Thaler, 1973). It was later characterized as a copper-binding peptide isolated from human plasma (Maquart et al., 1988). Most of the published research on it is preclinical: cell culture and animal models. This overview summarizes what that research reports, and at what level of evidence.
Chemistry: how GHK binds copper
GHK is a high-affinity copper(II) chelator. A structural study combining X-ray crystallography with several spectroscopic methods found that in solution Cu(II)-GHK forms a monomeric complex. The copper is held by three nitrogen atoms: the terminal amine, a backbone amide nitrogen, and the histidine imidazole. In the solid state the complex crystallizes as a dimer (Hureau et al., 2011). The same study found that copper exchanges quickly between GHK molecules, and that the complex is redox-inert under moderate conditions (Hureau et al., 2011).
Collagen synthesis in fibroblast cultures (in vitro)
A 1988 study reported that GHK-Cu stimulated collagen synthesis by cultured fibroblasts, the cells that produce the connective-tissue matrix. The effect was independent of any change in cell number, meaning the cells made more collagen rather than simply multiplying (Maquart et al., 1988). The authors also noted that the GHK sequence occurs within the α2(I) chain of type I collagen. They suggested the tripeptide might be released by proteases at a wound site, which they presented as a hypothesis, not a demonstrated mechanism (Maquart et al., 1988).
Connective tissue in a rat wound model (in vivo)
A 1993 follow-up tested GHK-Cu in rats, using a wound-chamber model: small stainless-steel mesh cylinders implanted under the skin, into which the test solution or saline was applied. Chambers treated with GHK-Cu showed concentration-dependent increases in dry weight, DNA, total protein, collagen and glycosaminoglycans. Collagen synthesis was stimulated about twice as much as that of non-collagen proteins. Messenger RNA for type I and type III collagen increased, while TGF-β mRNA did not. A control tripeptide (Glu-His-Pro) had no significant effect (Maquart et al., 1993).
The broader literature, read carefully
A 2018 review by GHK's original discoverer and a co-author surveys a much wider set of reported actions, including tissue-repair findings across several organ models, and gene-expression data suggesting GHK influences many biochemical pathways (Pickart & Margolina, 2018). It is a useful map of the hypotheses the field is pursuing. But it is a review written by the compound's discoverer, much of what it covers rests on cell-culture and gene-expression work, and its broad conclusions go well beyond what the individual studies above establish. Read it as a guide to the primary literature, not a substitute for it.
References
- Pickart L, Thaler MM. Tripeptide in human serum which prolongs survival of normal liver cells and stimulates growth in neoplastic liver. Nat New Biol. 1973;243(124):85-7. PMID: 4349963
- Maquart FX, Pickart L, Laurent M, et al. Stimulation of collagen synthesis in fibroblast cultures by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+. FEBS Lett. 1988;238(2):343-6. PMID: 3169264
- Maquart FX, Bellon G, Chaqour B, et al. In vivo stimulation of connective tissue accumulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+ in rat experimental wounds. J Clin Invest. 1993;92(5):2368-76. PMID: 8227353
- Hureau C, Eury H, Guillot R, et al. X-ray and solution structures of Cu(II) GHK and Cu(II) DAHK complexes: influence on their redox properties. Chemistry. 2011;17(36):10151-60. PMID: 21780203
- Pickart L, Margolina A. Regenerative and protective actions of the GHK-Cu peptide in the light of the new gene data. Int J Mol Sci. 2018;19(7):1987. PMID: 29986520