Expression of Glycosaminoglycans and Small Proteoglycans in Wounds: Modulation by the Tripeptide–Copper Complex Glycyl-L-Histidyl-L-Lysine-Cu2+
Open accessAbstract
Glycyl-histidyl-lysine-Cu(2+) is a tripeptide-copper complex previously shown to be an activator of wound healing. We have investigated the effects of glycyl-histidyl-lysine-Cu(2+) on the synthesis of glycosaminoglycans and small proteoglycans in a model of rat experimental wounds and in rat dermal fibroblast cultures. Repeated injections of glycyl-histidyl-lysine-Cu(2+) (2 mg per injection) stimulated the wound tissue production, as appreciated by dry weight and total protein measurements. This stimulation was accompanied by an increased production of type I collagen and glycosaminoglycans (assessed, respectively, by hydroxyproline and uronic acid contents of the chamber). Electrophoretic analysis of wound tissue glycosaminoglycans showed an accumulation of chondroitin sulfate and dermatan sulfate in control wound chambers, whereas the proportion of hyaluronic acid decreased with time. The accumulation of chondroitin sulfate and dermatan sulfate was enhanced by glycyl-histidyl-lysine-Cu(2+) treatment. The expression of two small proteoglycans of the dermis, decorin and biglycan, was analyzed by northern blot. The biglycan mRNA steady-state level in the chamber was maximal at day 12, whereas the decorin mRNA increased progressively until the end of the experiment (day 22). Glycyl-histidyl-lysine-Cu(2+) treatment increased the mRNA level of decorin and decreased those of biglycan. In dermal fibroblast cultures, the stimulation of decorin expression by glycyl-histidyl-lysine-Cu(2+) was also found. In contrast, biglycan expression was not modified. These results show that the expression of different proteoglycans in wound tissue are regulated in a different manner during wound healing. The glycyl-histidyl-lysine-Cu(2+) complex is able to modulate the expression of the extracellular matrix macromolecules differently during the wound repair process.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
GHK-Cu stimulated the production of collagen, dermatan sulfate, chondroitin sulfate, and the small proteoglycan decorin.
“In 2000, the same group demonstrated, using mRNA analysis, that GHK-Cu stimulated the production of collagen, dermatan sulfate, chondroitin sulfate, and the small proteoglycan decorin [27].”
From GHK-Cu may Prevent Oxidative Stress in Skin by Regulating Copper and Modifying Expression of Numerous Antioxidant Genes (2015) · cites this paper as [27]
The paper reports increased collagen content in wound chambers and increased chondroitin sulfate, dermatan sulfate, and decorin expression or production. However, the citing sentence overstates the role of mRNA analysis: the paper measured collagen and glycosaminoglycans biochemically, while mRNA analysis was used for decorin. The decisive passages are in “GHK-Cu increases collagen and GAG accumulation in wound chambers” and “GHK-Cu modulates the distribution of GAG in wound tissue”; page numbers were not supplied. (LLM, conf=0.87)
Experimental — accuracy not yet measuredGHK stimulates synthesis of collagen, selected glycosaminoglycans and small proteoglycan decorin.
“A number of experiments established that GHK stimulates synthesis of collagen, selected glycosaminoglycans and small proteoglycan decorin [8,9].”
From Regenerative and Protective Actions of the GHK-Cu Peptide in the Light of the New Gene Data (2018) · cites this paper as [8]
The wound-chamber results report increased collagen content and GAG accumulation after GHK-Cu treatment, and the paper states that chondroitin sulfate and dermatan sulfate production increased. Its fibroblast results also show increased decorin production. The experiments tested the copper complex GHK-Cu, not GHK alone, and measured collagen accumulation rather than collagen synthesis directly (pages not specified in our copy). (LLM, conf=0.84)
Experimental — accuracy not yet measuredGHK-Cu activates the synthesis of matrix compounds in vivo that are needed for resistant new tissue.
“It is also involved in the activation of the synthesis of matrix compounds in vivo, which are critical for the formation of a resistant new tissue [12–13].”
From The potential of GHK as an anti-aging peptide (2020) · cites this paper as [12]
GHK stimulates production of decorin in early wound healing experiments.
“In early wound healing experiments, GHK was found to stimulate production of a small, leucinerich proteoglycan, decorin.”
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 [36]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
PROTEIN MEASUREMENT WITH THE FOLIN PHENOL REAGENT
Lowry, O. H., Rosebrough, N., Farr, A. L., & Randall, R. (1951) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)52451-6 · Cited by 315,771 · see citing works
Molecular cloning: A laboratory manual
Deininger, P. L. (1990) · Analytical Biochemistry · doi:10.1016/0003-2697(90)90595-z · Cited by 84,684 · see citing works
Single-Step Method of RNA Isolation by Acid Guanidinium Thiocyanate–Phenol–Chloroform Extraction
Chomczynski, P., & Sacchi, N. (1987) · Analytical Biochemistry · doi:10.1006/abio.1987.9999 · Cited by 65,240 · see citing works
Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction
Chomczyński, P., & Sacchi, N. (1987) · Analytical Biochemistry · doi:10.1016/0003-2697(87)90021-2 · Cited by 47,092 · see citing works
A modified uronic acid carbazole reaction
Bitter, T., & Muir, H. M. (1962) · Analytical Biochemistry · doi:10.1016/0003-2697(62)90095-7 · Cited by 6,239 · see citing works
Fort, P., Marty, L., Piechaczyk, M., Sabrouty, S. R.-E., Dani, C., Jeanteur, P., & Blanchard, J. (1985) · Nucleic Acids Research · doi:10.1093/nar/13.5.1431 · Cited by 2,072 · see citing works
The Molecular and Cellular Biology of Wound Repair
Clark, R. A. F., & Henson, P. M. (1988) · Springer eBooks · doi:10.1007/978-1-4615-1795-5 · Cited by 1,524 · see citing works
Targeted Disruption of Decorin Leads to Abnormal Collagen Fibril Morphology and Skin Fragility
Danielson, K. G., Baribault, H., Holmes, D. F., Graham, H. K., Kadler, K. E., & Iozzo, R. V. (1997) · The Journal of Cell Biology · doi:10.1083/jcb.136.3.729 · Cited by 1,407 · see citing works
Enzymatic Methods for the Determination of Small Quantities of Isomeric Chondroitin Sulfates
Saito, H., Yamagata, T., & Suzuki, S. (1968) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)93575-1 · Cited by 1,369 · see citing works
Functions of hyaluronan in wound repair
Chen, W. Y. J., & Abatangelo, G. (1999) · Wound Repair and Regeneration · doi:10.1046/j.1524-475x.1999.00079.x · Cited by 1,089 · see citing works
Evidence for a prostate cancer susceptibility locus on the X chromosome.
Xu, J., Meyers, D. A., Freije, D., Isaacs, S. D., Wiley, K. E., Nusskern, D. R., Ewing, C. M., Wilkens, E. P., Bujnovszky, P., Bova, G. S., et al. (1998) · Nature Genetics · doi:10.1038/2477 · Cited by 690 · see citing works
Bianco, P., Fisher, L. W., Young, M. F., Termine, J. D., & Robey, P. G. (1990) · Journal of Histochemistry & Cytochemistry · doi:10.1177/38.11.2212616 · Cited by 667 · see citing works
Targeted disruption of the biglycan gene leads to an osteoporosis-like phenotype in mice
Xu, T., Bianco, P., Fisher, L. W., Longenecker, G., Smith, E. A., Goldstein, S. A., Bonadio, J. F., Boskey, A. L., Heegaard, A., Sommer, B., et al. (1998) · Nature Genetics · doi:10.1038/1746 · Cited by 612 · see citing works
Leucine-rich repeat glycoproteins of the extracellular matrix
Hocking, A. M., Shinomura, T., & McQuillan, D. J. (1998) · Matrix Biology · doi:10.1016/s0945-053x(98)90121-4 · Cited by 470 · see citing works
Antisera and cDNA probes to human and certain animal model bone matrix noncollagenous proteins
Fisher, L. W., Stubbs, J. T., & Young, M. F. (1995) · Acta Orthopaedica Scandinavica · doi:10.3109/17453679509157649 · Cited by 446 · see citing works
The Molecular and Cellular Biology of Wound Repair
Margolis, D. J. (1996) · Archives of Dermatology · doi:10.1001/archderm.1996.03890360125034 · Cited by 362 · see citing works
Expression of proteoglycans and hyaluronan during wound healing.
Oksala, O., Salo, T., Tammi, R., Häkkinen, L., Jalkanen, M., Inki, P., & Larjava, H. (1995) · Journal of Histochemistry & Cytochemistry · doi:10.1177/43.2.7529785 · Cited by 288 · see citing works
Determination of 2-deoxy-2-sulfoaminohexose content of mucopolysaccharides
Lagunoff, D., & Warren, G. H. (1962) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(62)90285-0 · Cited by 288 · see citing works
SPARC is a source of copper-binding peptides that stimulate angiogenesis
Lane, T. F., Iruela-Arispe, M. L., Johnson, R. S., & Sage, E. H. (1994) · The Journal of cell biology · doi:10.1083/jcb.125.4.929 · Cited by 249 · see citing works
Ceruloplasmin, Copper Ions, and Angiogenesis 2
Raju, K. S., Alessandri, G., Ziche, M., & Gullino, P. M. (1982) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/69.5.1183 · Cited by 241 · see citing works
Westergren‐Thorsson, G., Hernnäs, J., Särnstrand, B., Oldberg, Å., Heinegård, D. K., & Malmström, A. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116631 · Cited by 232 · see citing works
Dermatan Sulfate Released after Injury Is a Potent Promoter of Fibroblast Growth Factor-2 Function
Penc, S. F., Pomahač, B., Winkler, T., Dorschner, R. A., Eriksson, E. K., Herndon, M. E., & Gallo, R. L. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.43.28116 · Cited by 223 · see citing works
Lamme, E. N., de Vries, H. J. C., van Veen, H. A., Gabbiani, G., Westerhof, W., & Middelkoop, E. (1996) · Journal of Histochemistry & Cytochemistry · doi:10.1177/44.11.8918906 · Cited by 150 · see citing works
High and low molecular weight forms of endothelial cell growth factor.
Maciag, T., Hoover, G. A., & Weinstein, R. S. (1982) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)83778-x · Cited by 139 · see citing works
Sorenson, J. R. J. (1987) · Humana Press eBooks · doi:10.1007/978-1-4612-4584-1 · Cited by 126 · see citing works
Scott, P. G., Dodd, C. M., Tredget, E. E., Ghahary, A., & Rahemtulla, F. G. (1995) · Histopathology · doi:10.1111/j.1365-2559.1995.tb00249.x · Cited by 124 · see citing works
Dermatopontin interacts with transforming growth factor β and enhances its biological activity
Okamoto, O., Fujiwara, S., Abé, M., & Sato, Y. (1999) · Biochemical Journal · doi:10.1042/bj3370537 · Cited by 115 · see citing works
Pickart, L., & Thaler, M. (1973) · PubMed · Cited by 113 · see citing works
Maquart, F. X., Bellon, G., Chaqour, B., Wegrowski, J., Patt, L. M., Trachy, R. E., Monboisse, J. C., Chastang, F., Birembaut, P., & Gillery, P. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116842 · Cited by 110 · see citing works
Self-citationAlterations in proteoglycan synthesis common to healing wounds and tumors.
Yeo, T.-K., Brown, L. F., & Dvorak, H. F. (1991) · PubMed · Cited by 97 · see citing works
SCHILLING, J. A., Joel, W., & Hm, S. (1959) · PubMed · Cited by 84 · see citing works
Wegrowski, Y., Maquart, F. X., & Borel, J. P. (1992) · Life Sciences · doi:10.1016/0024-3205(92)90504-i · Cited by 72 · see citing works
Self-citationSiméon, A., Monier, F., Emonard, H., Gillery, P., Hornebeck, W., Maquart, F.-X., & Birembaut, P. (1999) · Journal of Investigative Dermatology · doi:10.1046/j.1523-1747.1999.00606.x · Cited by 68 · see citing works
Self-citation(1983) · PubMed · Cited by 63 · see citing works
The Murine Biglycan: Complete cDNA Cloning, Genomic Organization, Promoter Function, and Expression
Wegrowski, Y., Pillarisetti, J., Danielson, K. G., et al. (1995) · Genomics · doi:10.1006/geno.1995.0002 · Cited by 58 · see citing works
Self-citationWestergren‐Thorsson, G., Schmidtchen, A., Särnstrand, B., Fransson, L., & Malmström, A. (1992) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1992.tb16778.x · Cited by 56 · see citing works
Wegrowski, Y., Paltot, V., Gillery, P., et al. (1995) · Biochemical Journal · doi:10.1042/bj3070673 · Cited by 55 · see citing works
Self-citationMulder, G., Patt, L. M., Sanders, L., Rosenstock, J., Altman, M. I., Hanley, M. E., & Duncan, G. W. (1994) · Wound Repair and Regeneration · doi:10.1046/j.1524-475x.1994.20406.x · Cited by 53 · see citing works
Studies of fibroplasia in wound healing.
SCHILLING, J. A., Bv, F., & Radakovich, M. (1953) · PubMed · Cited by 47 · see citing works
The use of glycylhistidyllysine in culture systems
Pickart, L. (1981) · In Vitro Cellular & Developmental Biology - Plant · doi:10.1007/bf02633506 · Cited by 36 · see citing works
SCOTT, F. R., More, L., & Dhillon, A. P. (1995) · Histopathology · doi:10.1111/j.1365-2559.1995.tb00274.x · Cited by 35 · see citing works
Kimoto, S., Cheng, S., Zhang, S. F., & Avioli, L. V. (1994) · Endocrinology · doi:10.1210/endo.135.6.7988427 · Cited by 35 · see citing works
Yamamoto, K., Kusachi, S., Ninomiya, Y., Murakami, M., Doi, M., Takeda, K., Shinji, T., Higashi, T., Koide, N., & Tsuji, T. (1998) · Journal of Molecular and Cellular Cardiology · doi:10.1006/jmcc.1998.0737 · Cited by 23 · see citing works
An in vivo assay for chemoattractant activity.
Zetter, B. R., Rasmussen, N., & Brown, L. S. (1985) · PubMed · Cited by 23 · see citing works
Experimental influence of pharmacological agents on the regeneration of nervous tissue in vitro.
Grosse, G., & Lindner, G. (1980) · PubMed · Cited by 9 · see citing works
An automatic method of 4-hydroxyproline determination convenient for large series
Szymanowicz, G., & Laurain, G. (1981) · Analytical Biochemistry · doi:10.1016/0003-2697(81)90043-9 · Cited by 5 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Extracellular Matrix and Dermal Fibroblast Function in the Healing Wound
Tracy, L. E., Minasian, R. A., & Caterson, E. J. (2016) · Advances in Wound Care · doi:10.1089/wound.2014.0561 · Cited by 1,008 · see citing works
The human tri-peptide GHK and tissue remodeling
Pickart, L. (2008) · Journal of Biomaterials Science, Polymer Edition · doi:10.1163/156856208784909435 · Cited by 218 · see citing works
Role of topical peptides in preventing or treating aged skin
Gorouhi, F., & Maibach, H. I. (2009) · International Journal of Cosmetic Science · doi:10.1111/j.1468-2494.2009.00490.x · Cited by 193 · see citing works
Regenerative and Protective Actions of the GHK-Cu Peptide in the Light of the New Gene Data
Pickart, L., & Margolina, A. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19071987 · Cited by 158 · see citing works
GHK Peptide as a Natural Modulator of Multiple Cellular Pathways in Skin Regeneration
Pickart, L., Vasquez-Soltero, J. M., & Margolina, A. (2015) · BioMed Research International · doi:10.1155/2015/648108 · Cited by 144 · see citing works
Campbell, J. D., McDonough, J. E., Zeskind, J. E., Hackett, T. L., Pechkovsky, D. V., Brandsma, C.-A., Suzuki, M., Gosselink, J. V., Liu, G., Alekseyev, Y. O., et al. (2012) · Genome Medicine · doi:10.1186/gm367 · Cited by 128 · see citing works
Olczyk, P., Komosinska-Vassev, K., Winsz-Szczotka, K., Stojko, J., Klimek, K., & Kozma, E. M. (2013) · Evidence-Based Complementary and Alternative Medicine · doi:10.1155/2013/290675 · Cited by 65 · see citing works
Cangul, I. T., Gul, N. Y., Topal, A., & Yilmaz, R. (2006) · Veterinary Dermatology · doi:10.1111/j.1365-3164.2006.00551.x · Cited by 57 · see citing works
Healing of Chronic Wounds by Copper Oxide-Impregnated Wound Dressings—Case Series
Melamed, E., Kiambi, P., Okoth, D., Honigber, I., Tamir, E., & Borkow, G. (2021) · Medicina · doi:10.3390/medicina57030296 · Cited by 55 · see citing works
Copper–GHK increases integrin expression and p63 positivity by keratinocytes
Kang, Y.-A., Choi, H.-R., Na, J.-I., Huh, C.-H., Kim, M.-J., Youn, S.-W., Kim, K.-H., & Park, K.-C. (2009) · Archives of Dermatological Research · doi:10.1007/s00403-009-0942-x · Cited by 51 · see citing works
Pickart, L., Vasquez-Soltero, J., & Margolina, A. (2015) · Cosmetics · doi:10.3390/cosmetics2030236 · Cited by 48 · see citing works
Zhou, X.-M., Wang, G.-L., Wang, X.-B., Liu, L., Zhang, Q., Yin, Y., Wang, Q.-Y., Kang, J., & Hou, G. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00904 · Cited by 41 · see citing works
The potential of GHK as an anti-aging peptide
Department of Comparative Medicine, S. O. M., Dou, Y., Lee, A., Zhu, L., Morton, J., & Ladiges, W. (2020) · Aging Pathobiology and Therapeutics · doi:10.31491/apt.2020.03.014 · Cited by 33 · see citing works
“It is also involved in the activation of the synthesis of matrix compounds in vivo, which are critical for the formation of a resistant new tissue [12-13].”
BackgroundBeretta, G., Artali, R., Regazzoni, L., Panigati, M., & Facino, R. M. (2007) · Chemical Research in Toxicology · doi:10.1021/tx700185s · Cited by 30 · see citing works
Fu, S., Cheuk, Y., Chiu, W. V., Yung, S., Rolf, C. G., & Chan, K. (2015) · Journal of Orthopaedic Research · doi:10.1002/jor.22831 · Cited by 25 · see citing works
MAZUROWSKA, L., & MOJSKI, M. (2007) · Talanta · doi:10.1016/j.talanta.2006.11.034 · Cited by 23 · see citing works
Pickart, L., Vasquez-Soltero, J. M., Pickart, F. D., & Majnarich, J. (2014) · Journal of Analytical Oncology · doi:10.6000/1927-7229.2014.03.02.2 · Cited by 12 · see citing works
A gene expression signature of emphysematous lung destruction and its reversal by the tripeptide GHK
Campbell, J. D., McDonough, J. E., Zeskind, J. E., Hackett, T. L., Pechkovsky, D. V., Brandsma, C.-A., Suzuki, M., Gosselink, J. V., Liu, G., Alekseyev, Y. O., et al. (2012) · Genome Medicine · doi:10.1186/gm368 · Cited by 5 · see citing works
Pickart, L., & Margolina, A. (2021) · OBM Genetics · doi:10.21926/obm.genet.2102128 · Cited by 3 · see citing works
- Authors
- Siméon, A., Wegrowski, Y., Bontemps, Y., & Maquart, F.-X.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Maquart, François-Xavier
- Venue
- Journal of Investigative Dermatology
- Publisher
- Elsevier BV
- Published
- 2000-12
- Volume
- 115
- Issue
- 6
- Pages
- 962-968
- ISSN
- 0022-202X (ISSN-L)
- OpenAlex
- W2048604783
- Cited by
- 119
- References
- 46
- Citations by year
- 2026: 11 · 2025: 4 · 2024: 5 · 2023: 8 · 2022: 6 · 2021: 5 · 2020: 6 · 2019: 3 · 2018: 4 · 2017: 3 · 2016: 5 · 2015: 8 · 2014: 5 · 2013: 3 · 2012: 5
- FWCI
- 0.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- 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 › Rehabilitation › Wound Healing and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- wound healing, glycosaminoglycans, small proteoglycans, decorin, biglycan, chondroitin sulfate, dermatan sulfate, hyaluronic acid, type I collagen, extracellular matrix, dermal fibroblasts, gene expression regulation
- MeSH terms
- Animals, Fibroblasts, Glycosaminoglycans, Male, Oligopeptides, Proteoglycans, Wound Healing, Wounds and Injuries, Transforming Growth Factor beta, Extracellular Matrix Proteins, Rats, Sprague-Dawley, Rats, Decorin, Biglycan
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
