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Synergistic effect of copper and amino acid mixtures on the production of extracellular matrix proteins in skin fibroblasts

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Abstract

The stimulation of extracellular matrix (ECM) protein production is an interesting target to maintain normal skin structure and delay skin aging. Copper has been shown to stimulate ECM protein synthesis by activating lysyl oxidase. Although copper increases elastin and collagen synthesis, the effect of copper and amino acid mixtures on gene expression and protein synthesis changes relating to the ECM have not been fully investigated. In this study, we showed that copper ions (Cu2+) and amino acid mixtures significantly increased the expression of genes and proteins related to the ECM in human dermal fibroblasts. The expression of genes involved in ECM production was evaluated through quantitative polymerase chain reaction in the presence of amino acid mixtures containing different Cu2+ concentrations. Cu2+ dose-dependently increased the gene expression of elastin and collagen I. In addition, a mixture of amino acids and Cu2+ increased the protein expression of elastin and collagen I. We further evaluated the effect of Cu2+ with or without amino acids. Although Cu2+ treatment increased the expression of genes encoding ECM proteins, the Cu2+ treatment without amino acids did not increase protein expression in the ECM. Our results demonstrated the synergistic effects of amino acids and a Cu2+ mixture on ECM protein synthesis in dermal fibroblasts.

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References

  1. Bukhari SNA, Roswandi NL, Waqas M, Habib H, Hussain F, Khan S, Sohail M, Ramli NA, Thu HE, Hussain Z (2018) Hyaluronic acid, a promising skin rejuvenating biomedicine: a review of recent updates and pre-clinical and clinical investigations on cosmetic and nutricosmetic effects. Int J Biol Macromol 120(Pt B):1682–1695. https://doi.org/10.1016/j.ijbiomac.2018.09.188

    Article  CAS  PubMed  Google Scholar 

  2. Cai L, Xiong X, Kong X, Xie J (2017) The role of the lysyl oxidases in tissue repair and remodeling: a concise review. Tissue Eng Regen Med 14(1):15–30. https://doi.org/10.1007/s13770-016-0007-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Croce MA, Dyne K, Boraldi F, Quaglino D Jr, Cetta G, Tiozzo R, Pasquali Ronchetti I (2001) Hyaluronan affects protein and collagen synthesis by in vitro human skin fibroblasts. Tissue Cell 33(4):326–331. https://doi.org/10.1054/tice.2001.0180

    Article  CAS  PubMed  Google Scholar 

  4. De Servi B, Orlandini A, Caviola E, Meloni M (2018) Amino acid and hyaluronic acid mixtures differentially regulate extra cellular matrix genes in cultured human fibroblasts. J Biol Regul Homeost Agents 32(3):517–527

    PubMed  Google Scholar 

  5. Karna E, Miltyk W, Wolczynski S, Palka JA (2001) The potential mechanism for glutamine-induced collagen biosynthesis in cultured human skin fibroblasts. Comp Biochem Physiol B Biochem Mol Biol 130(1):23–32. https://doi.org/10.1016/s1096-4959(01)00400-6

    Article  CAS  PubMed  Google Scholar 

  6. Karna E, Szoka L, Huynh TYL, Palka JA (2020) Proline-dependent regulation of collagen metabolism. Cell Mol Life Sci 77(10):1911–1918. https://doi.org/10.1007/s00018-019-03363-3

    Article  CAS  PubMed  Google Scholar 

  7. Kothapalli CR, Ramamurthi A (2009) Copper nanoparticle cues for biomimetic cellular assembly of crosslinked elastin fibers. Acta Biomater 5(2):541–553. https://doi.org/10.1016/j.actbio.2008.09.004

    Article  CAS  PubMed  Google Scholar 

  8. Kular JK, Basu S, Sharma RI (2014) The extracellular matrix: structure, composition, age-related differences, tools for analysis and applications for tissue engineering. J Tissue Eng 5:2041731414557112. https://doi.org/10.1177/2041731414557112

    Article  PubMed  PubMed Central  Google Scholar 

  9. Li P, Wu G (2018) Roles of dietary glycine, proline, and hydroxyproline in collagen synthesis and animal growth. Amino Acids 50(1):29–38. https://doi.org/10.1007/s00726-017-2490-6

    Article  CAS  PubMed  Google Scholar 

  10. Murad S, Grove D, Lindberg KA, Reynolds G, Sivarajah A, Pinnell SR (1981) Regulation of collagen synthesis by ascorbic acid. Proc Natl Acad Sci 78(5):2879–2882. https://doi.org/10.1073/pnas.78.5.2879

    Article  CAS  PubMed  Google Scholar 

  11. Murakami H, Shimbo K, Inoue Y, Takino Y, Kobayashi H (2012) Importance of amino acid composition to improve skin collagen protein synthesis rates in UV-irradiated mice. Amino Acids 42(6):2481–2489. https://doi.org/10.1007/s00726-011-1059-z

    Article  CAS  PubMed  Google Scholar 

  12. Ogen-Shtern N, Chumin K, Cohen G, Borkow G (2020) Increased pro-collagen 1, elastin, and TGF-beta1 expression by copper ions in an ex-vivo human skin model. J Cosmet Dermatol 19(6):1522–1527. https://doi.org/10.1111/jocd.13186

    Article  PubMed  Google Scholar 

  13. Panwar P, Butler GS, Jamroz A, Azizi P, Overall CM, Bromme D (2018) Aging-associated modifications of collagen affect its degradation by matrix metalloproteinases. Matrix Biol 65:30–44. https://doi.org/10.1016/j.matbio.2017.06.004

    Article  CAS  PubMed  Google Scholar 

  14. Parrado C, Mercado-Saenz S, Perez-Davo A, Gilaberte Y, Gonzalez S, Juarranz A (2019) Environmental stressors on skin aging Mechanistic Insights. Front Pharmacol 10:759. https://doi.org/10.3389/fphar.2019.00759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Philips N, Hwang H, Chauhan S, Leonardi D, Gonzalez S (2010) Stimulation of cell proliferation and expression of matrixmetalloproteinase-1 and interluekin-8 genes in dermal fibroblasts by copper. Connect Tissue Res 51(3):224–229. https://doi.org/10.3109/03008200903288431

    Article  CAS  PubMed  Google Scholar 

  16. Philips N, Samuel P, Parakandi H, Gopal S, Siomyk H, Ministro A, Thompson T, Borkow G (2012) Beneficial regulation of fibrillar collagens, heat shock protein-47, elastin fiber components, transforming growth factor-beta1, vascular endothelial growth factor and oxidative stress effects by copper in dermal fibroblasts. Connect Tissue Res 53(5):373–378. https://doi.org/10.3109/03008207.2012.665970

    Article  CAS  PubMed  Google Scholar 

  17. Quan T, Fisher GJ (2015) Role of age-associated alterations of the dermal extracellular matrix microenvironment in human skin aging: a mini-review. Gerontology 61(5):427–434. https://doi.org/10.1159/000371708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ricard-Blum S (2011) The collagen family. Cold Spring Harb Perspect Biol 3(1):a004978. https://doi.org/10.1101/cshperspect.a004978

    Article  PubMed  PubMed Central  Google Scholar 

  19. Rognoni E, Watt FM (2018) Skin cell heterogeneity in development, wound healing, and cancer. Trends Cell Biol 28(9):709–722. https://doi.org/10.1016/j.tcb.2018.05.002

    Article  PubMed  PubMed Central  Google Scholar 

  20. Rucker RB, Kosonen T, Clegg MS, Mitchell AE, Rucker BR, Uriu-Hare JY, Keen CL (1998) Copper, lysyl oxidase, and extracellular matrix protein cross-linking. Am J Clin Nutr 67(5 Suppl):996S-1002S. https://doi.org/10.1093/ajcn/67.5.996S

    Article  CAS  PubMed  Google Scholar 

  21. Rucker RB, Parker HE, Rogler JC (1969) Effect of copper deficiency on chick bone collagen and selected bone enzymes. J Nutr 98(1):57–63. https://doi.org/10.1093/jn/98.1.57

    Article  CAS  PubMed  Google Scholar 

  22. Scarano A, Sbarbati A, Amore R, Iorio EL, Ferraro G, Marchetti M, Amuso D (2020) The role of hyaluronic acid and amino acid against the aging of the human skin: a clinical and histological study. J Cosmet Dermatol. https://doi.org/10.1111/jocd.13811

    Article  PubMed  Google Scholar 

  23. Shin JW, Kwon SH, Choi JY, Na JI, Huh CH, Choi HR, Park KC (2019) Molecular mechanisms of dermal aging and antiaging approaches. Int J Mol Sci. https://doi.org/10.3390/ijms20092126

    Article  PubMed  PubMed Central  Google Scholar 

  24. Shoulders MD, Raines RT (2009) Collagen structure and stability. Annu Rev Biochem 78:929–958. https://doi.org/10.1146/annurev.biochem.77.032207.120833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Siegel RC, Pinnell SR, Martin GR (1970) Cross-linking of collagen and elastin. Properties of lysyl oxidase. Biochemistry 9(23):4486–4492. https://doi.org/10.1021/bi00825a004

    Article  CAS  PubMed  Google Scholar 

  26. Taszkun I, Tomaszewska E, Dobrowolski P, Zmuda A, Sitkowski W, Muszynski S (2019) Evaluation of collagen and elastin content in skin of multiparous minks receiving feed contaminated with deoxynivalenol (DON, vomitoxin) with or without bentonite supplementation. Animals. https://doi.org/10.3390/ani9121081

    Article  PubMed  Google Scholar 

  27. Tracy LE, Minasian RA, Caterson EJ (2016) Extracellular matrix and dermal fibroblast function in the healing wound. Adv Wound Care 5(3):119–136. https://doi.org/10.1089/wound.2014.0561

    Article  Google Scholar 

  28. Varani J, Dame MK, Rittie L, Fligiel SE, Kang S, Fisher GJ, Voorhees JJ (2006) Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation. Am J Pathol 168(6):1861–1868. https://doi.org/10.2353/ajpath.2006.051302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Vrhovski B, Weiss AS (1998) Biochemistry of tropoelastin. Eur J Biochem 258(1):1–18. https://doi.org/10.1046/j.1432-1327.1998.2580001.x

    Article  CAS  PubMed  Google Scholar 

  30. Watt FM, Fujiwara H (2011) Cell-extracellular matrix interactions in normal and diseased skin. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a005124

    Article  PubMed  PubMed Central  Google Scholar 

  31. Weihermann AC, Lorencini M, Brohem CA, de Carvalho CM (2017) Elastin structure and its involvement in skin photoageing. Int J Cosmet Sci 39(3):241–247. https://doi.org/10.1111/ics.12372

    Article  CAS  PubMed  Google Scholar 

  32. Zhang S, Duan E (2018) Fighting against skin aging: the way from bench to bedside. Cell Transplant 27(5):729–738. https://doi.org/10.1177/0963689717725755

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by Korea Institute of Startup and Entrepreneurship Development and Pusan National University Research Grant, 2020.

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Authors and Affiliations

  1. College of Pharmacy, Pusan National University, 2, Busandaehak-ro 63 beon-gil, Geumjeong-gu, Busan, 46241, Republic of Korea

    Ki Wung Chung

  2. College of Pharmacy, Kyungsung University, Busan, 48434, Republic of Korea

    Seh Hyon Song

  3. Elastic Lab Inc., 1905, Cheonbyeonu-ro 339, Dong-gu, Gwangju, Republic of Korea

    Man-seok Kim

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  1. Ki Wung Chung
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KWC: Performed experiments, writing, funding acquisition. SHS: Methodology, performed experiments, materials provided. MK: Conceptualization, funding acquisition.

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Correspondence to Ki Wung Chung.

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Chung, K.W., Song, S.H. & Kim, Ms. Synergistic effect of copper and amino acid mixtures on the production of extracellular matrix proteins in skin fibroblasts. Mol Biol Rep 48, 3277–3284 (2021). https://doi.org/10.1007/s11033-021-06403-z

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