Reduced Expression of Connective Tissue Growth Factor (CTGF/CCN2) Mediates Collagen Loss in Chronologically Aged Human Skin
Open accessAbstract
Reduced production of type I procollagen is a prominent feature of chronologically aged human skin. Connective tissue growth factor (CTGF/CCN2), a downstream target of the transforming growth factor-beta (TGF-beta)/Smad pathway, is highly expressed in numerous fibrotic disorders, in which it is believed to stimulate excessive collagen production. CTGF is constitutively expressed in normal human dermis in vivo, suggesting that CTGF is a physiological regulator of collagen expression. We report here that the TGF-beta/Smad/CTGF axis is significantly reduced in dermal fibroblasts, the major collagen-producing cells, in aged (> or = 80 years) human skin in vivo. In primary human skin fibroblasts, neutralization of endogenous TGF-beta or knockdown of CTGF substantially reduced the expression of type I procollagen mRNA, protein, and promoter activity. In contrast, overexpression of CTGF stimulated type I procollagen expression, and increased promoter activity. Inhibition of TGF-beta receptor kinase, knockdown of Smad4, or overexpression of inhibitory Smad7 abolished CTGF stimulation of type I procollagen expression. However, CTGF did not stimulate Smad3 phosphorylation or Smad3-dependent transcriptional activity. These data indicate that in human skin fibroblasts, type I procollagen expression is dependent on endogenous production of both TGF-beta and CTGF, which act through interdependent yet distinct mechanisms. Downregulation of the TGF-beta/Smad/CTGF axis likely mediates reduced type I procollagen expression in aged human skin in vivo.
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?
Skin aging is characterized by impaired wound healing, atrophy, reduced tensile strength and wrinkle formation, marked loss in skin structural integrity and in collagen and elastic fibres, with weakening in the fibre network, due to dysfunctional fibroblasts.
“Particularly for skin aging, an event characterized by impaired wound healing, atrophy, reduced tensile strength and wrinkle formation, a marked loss in skin structural integrity and in collagen and elastic fibres, with weakening in the fibre network, has been reported, due to dysfunctional fibroblasts [34,35].”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [35]
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
TGF-β signaling and the fibrotic response
Leask, A., & Abraham, D. J. (2004) · The FASEB Journal · doi:10.1096/fj.03-1273rev · Cited by 2,319 · see citing works
Mechanisms of photoaging and chronological skin aging
Fisher, G. J., Kang, S., Varani, J., Bata-Csorgo, Z., Wan, Y., Datta, S., & Voorhees, J. J. (2002) · Archives of Dermatology · doi:10.1001/archderm.138.11.1462 · Cited by 1,849 · see citing works
Self-citationPathophysiology of Premature Skin Aging Induced by Ultraviolet Light
Fisher, G. J., Wang, Z., Datta, S. C., Varani, J., Kang, S., & Voorhees, J. J. (1997) · New England Journal of Medicine · doi:10.1056/nejm199711133372003 · Cited by 1,501 · see citing works
Self-citationDecreased Collagen Production in Chronologically Aged Skin
Varani, J., Dame, M. K., Rittie, L., Fligiel, S. E. G., Kang, S., Fisher, G. J., & Voorhees, J. J. (2006) · The American Journal of Pathology · doi:10.2353/ajpath.2006.051302 · Cited by 910 · see citing works
Self-citationConnective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-β
Abreu, J. G., Ketpura, N. I., Reversade, B., & Robertis, E. M. D. (2002) · Nature Cell Biology · doi:10.1038/ncb826 · Cited by 901 · see citing works
Bradham, D. M., Igarashi, A., Potter, R. L., & Grotendorst, G. R. (1991) · The Journal of Cell Biology · doi:10.1083/jcb.114.6.1285 · Cited by 878 · see citing works
Connective tissue growth factor: a mediator of TGF-β action on fibroblasts
Grotendorst, G. R. (1997) · Cytokine & Growth Factor Reviews · doi:10.1016/s1359-6101(97)00010-5 · Cited by 754 · see citing works
Frazier, K. S., Williams, S. J., Kothapalli, D., Klapper, H., & Grotendorst, G. R. (1996) · Journal of Investigative Dermatology · doi:10.1111/1523-1747.ep12363389 · Cited by 750 · see citing works
Ivković, S., Yoon, B. S., Popoff, S. N., Safadi, F. F., Libuda, D. E., Stephenson, R. C., Daluiski, A., & Lyons, K. M. (2003) · Development · doi:10.1242/dev.00505 · Cited by 705 · see citing works
Laping, N. J., Grygielko, E. T., Mathur, A., Butter, S., Bomberger, J. M., Tweed, C. W., Martin, W., Fornwald, J. A., Lehr, R. V., Harling, J. D., et al. (2002) · Molecular Pharmacology · doi:10.1124/mol.62.1.58 · Cited by 638 · see citing works
Duncan, M. R., Frazier, K. S., Abramson, S., Williams, S. J., Klapper, H., Huang, X., & Grotendorst, G. R. (1999) · The FASEB Journal · doi:10.1096/fasebj.13.13.1774 · Cited by 628 · see citing works
The Connective Tissue Growth Factor/Cysteine- Rich 61/Nephroblastoma Overexpressed (CCN) Family
Brigstock, D. R. (1999) · Endocrine Reviews · doi:10.1210/edrv.20.2.0360 · Cited by 588 · see citing works
Looking Older: Fibroblast Collapse and Therapeutic Implications
Fisher, G. J., Varani, J., & Voorhees, J. J. (2008) · Archives of Dermatology · doi:10.1001/archderm.144.5.666 · Cited by 540 · see citing works
Self-citationGrotendorst, G. R., Okochi, H., & Hayashi, N. (1996) · PubMed · Cited by 525 · see citing works
Fisher, G. J., Quan, T., Purohit, T., Shao, Y., Cho, M. K., He, T., Varani, J., Kang, S., & Voorhees, J. J. (2009) · The American Journal of Pathology · doi:10.2353/ajpath.2009.080599 · Cited by 487 · see citing works
Self-citationBabic, A. M., Chen, C.-C., & Lau, L. F. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.4.2958 · Cited by 445 · see citing works
CTGF and SMADs, Maintenance of Scleroderma Phenotype Is Independent of SMAD Signaling
Holmes, A. M., Abraham, D., Sa, S., Shiwen, X., Black, C. M., & Leask, A. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010149200 · Cited by 423 · see citing works
Fisher, G. J., Talwar, H. S., Lin, J., Lin, P., McPhillips, F., Wang, Z., Li, X., Wan, Y., Kang, S., & Voorhees, J. J. (1998) · Journal of Clinical Investigation · doi:10.1172/jci2153 · Cited by 392 · see citing works
Self-citationQuan, T., He, T., Kang, S., Voorhees, J. J., & Fisher, G. J. (2004) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63337-8 · Cited by 386 · see citing works
Self-citationShiwen, X., Leask, A., & Abraham, D. (2008) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2008.01.002 · Cited by 369 · see citing works
Chen, C.-C., Chen, N., & Lau, L. F. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008087200 · Cited by 305 · see citing works
Fisher, G. J., Datta, S. C., Wang, Z., Li, X.-Y., Quan, T., Chung, J. H., Kang, S., & Voorhees, J. J. (2000) · Journal of Clinical Investigation · doi:10.1172/jci9362 · Cited by 304 · see citing works
Self-citationConnective Tissue Growth Factor Gene Regulation
Leask, A., Holmes, A. M., Black, C. M., & Abraham, D. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m210366200 · Cited by 304 · see citing works
The Angiogenic Factor Cyr61 Activates a Genetic Program for Wound Healing in Human Skin Fibroblasts
Chen, C.-C., Mo, F.-E., & Lau, L. F. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m107666200 · Cited by 300 · see citing works
Halder, S. K., Beauchamp, R. D., & Datta, P. K. (2005) · Neoplasia · doi:10.1593/neo.04640 · Cited by 288 · see citing works
Gupta, S. K., Clarkson, M., Duggan, J., & Brady, H. R. (2000) · Kidney International · doi:10.1046/j.1523-1755.2000.00301.x · Cited by 286 · see citing works
Fligiel, S., Varani, J., Datta, S. C., Kang, S., Fisher, G. J., & Voorhees, J. J. (2003) · Journal of Investigative Dermatology · doi:10.1046/j.1523-1747.2003.12148.x · Cited by 283 · see citing works
Self-citationLeask, A., & Abraham, D. (2003) · Biochemistry and Cell Biology · doi:10.1139/o03-069 · Cited by 260 · see citing works
Abraham, D., Shiwen, X., Black, C. M., Sa, S., Xu, Y., & Leask, A. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.20.15220 · Cited by 255 · see citing works
Schober, J. M., Chen, N., Grzeszkiewicz, T. M., Jovanovic, I., Emeson, E. E., Ugarova, T. P., Ye, R. D., Lau, L. F., & Lam, S. C.-T. (2002) · Blood · doi:10.1182/blood.v99.12.4457 · Cited by 242 · see citing works
Jedsadayanmata, A., Chen, C.-C., Kireeva, M. L., Lau, L. F., & Lam, S. C.-T. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.34.24321 · Cited by 204 · see citing works
Cellular, Immunologic and Biochemical Characterization of Topical Retinoic Acid—Treated Human Skin
Fisher, G. J., Esmann, J., Grifliths, C. E. M., Talwar, H. S., Duell, E. A., Hammerberg, C., Elder, J. T., Karabin, G. D., Nickoloff, B. J., Cooper, K. D., et al. (1991) · Journal of Investigative Dermatology · doi:10.1111/1523-1747.ep12470632 · Cited by 182 · see citing works
Self-citationChung, J. H., Kang, S., Varani, J., Lin, J., Fisher, G. J., & Voorhees, J. J. (2000) · Journal of Investigative Dermatology · doi:10.1046/j.1523-1747.2000.00009.x · Cited by 181 · see citing works
Self-citationVerrecchia, F., Pessah, M., Atfi, A., & Mauviel, A. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m005310200 · Cited by 170 · see citing works
Ultraviolet Irradiation Alters Transforming Growth Factor β/Smad Pathway in Human Skin In Vivo
Quan, T., He, T., Kang, S., Voorhees, J. J., & Fisher, G. J. (2002) · Journal of Investigative Dermatology · doi:10.1046/j.1523-1747.2002.01834.x · Cited by 169 · see citing works
Self-citationCCN2 (Connective Tissue Growth Factor) Promotes Fibroblast Adhesion to Fibronectin
Chen, Y., Abraham, D., Shiwen, X., Pearson, J. D., Black, C. M., Lyons, K. M., & Leask, A. (2004) · Molecular Biology of the Cell · doi:10.1091/mbc.e04-06-0490 · Cited by 167 · see citing works
Quan, T., He, T., Voorhees, J. J., & Fisher, G. J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010835200 · Cited by 167 · see citing works
Self-citationRole of connective tissue growth factor in the pathogenesis of diabetic nephropathy
Wahab, N. A., Yevdokimova, N. Y., Weston, B. S., Roberts, T., Xin Jun, L. I., BRINKMAN, H., & Mason, R. M. (2001) · Biochemical Journal · doi:10.1042/0264-6021:3590077 · Cited by 163 · see citing works
CCN2 Is Necessary for Adhesive Responses to Transforming Growth Factor-β1 in Embryonic Fibroblasts
Xu, S., Stanton, L., Kennedy, L., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m511343200 · Cited by 150 · see citing works
TGF-β and CTGF have overlapping and distinct fibrogenic effects on human renal cells
Gore-Hyer, E., Shegogue, D., Markiewicz, M., Lo, S., Hazen‐Martin, D. J., Greene, E. L., Grotendorst, G. R., & Trojanowska, M. E. (2002) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00007.2002 · Cited by 145 · see citing works
Oncostatin M Stimulates Transcription of the Human α2(I) Collagen Gene via the Sp1/Sp3-binding Site
Ihn, H., LeRoy, E. C., & Trojanowska, M. E. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.39.24666 · Cited by 141 · see citing works
Quan, T., He, T., Shao, Y., Lin, L., Kang, S., Voorhees, J. J., & Fisher, G. J. (2006) · American Journal Of Pathology · doi:10.2353/ajpath.2006.060128 · Cited by 130 · see citing works
Self-citationLeivonen, S., Häkkinen, L., Liu, D., & Kähäri, V. (2005) · Journal of Investigative Dermatology · doi:10.1111/j.0022-202x.2005.23750.x · Cited by 118 · see citing works
Chujo, S., Shirasaki, F., Kawara, S., Inagaki, Y., Kinbara, T., Inaoki, M., Takigawa, M., & Takehara, K. (2004) · Journal of Cellular Physiology · doi:10.1002/jcp.20251 · Cited by 117 · see citing works
Wu, Q., Twigg, S., Chen, X., et al. (2004) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00179.2004 · Cited by 111 · see citing works
Heng, E. C. K., Huang, Y., Black, S. A., & Trackman, P. C. (2006) · Journal of Cellular Biochemistry · doi:10.1002/jcb.20810 · Cited by 104 · see citing works
Nishida, T., Kubota, S., Fukunaga, T., et al. (2003) · Journal of Cellular Physiology · doi:10.1002/jcp.10277 · Cited by 100 · see citing works
Yang, M., Huang, H.-C., Li, J., et al. (2004) · The FASEB Journal · doi:10.1096/fj.04-2357fje · Cited by 100 · see citing works
Quan, T., He, T., Voorhees, J. J., & Fisher, G. J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m409647200 · Cited by 97 · see citing works
Self-citationRole of connective tissue growth factor in the pathogenesis of diabetic nephropathy
Wahab, N. A., Yevdokimova, N. Y., Weston, B. S., et al. (2001) · Biochemical Journal · doi:10.1042/bj3590077 · Cited by 96 · see citing works
Nishida, T., Kawaki, H., Baxter, R. M., et al. (2007) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-007-0005-z · Cited by 90 · see citing works
The CCN family of genes: a perspective on CCN biology and therapeutic potential
Yeger, H., & Perbal, B. (2007) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-008-0022-6 · Cited by 88 · see citing works
Quan, T., He, T., Kang, S., Voorhees, J. J., & Fisher, G. J. (2002) · Journal of Investigative Dermatology · doi:10.1046/j.0022-202x.2001.01678.x · Cited by 80 · see citing works
Self-citationFisher, G. J., Henderson, P., Voorhees, J. J., et al. (1991) · Journal of Cellular Physiology · doi:10.1002/jcp.1041460216 · Cited by 56 · see citing works
Self-citation森, 俊. (1999) · Kanazawa University Repository for Academic Resources (DSpace) (Kanazawa University) · doi:10.11501/3171584 · Cited by 48 · see citing works
Boehm, J. R., Kutz, S. M., Sage, E. H., Staiano‐Coico, L., & Higgins, P. J. (1999) · Journal of Cellular Physiology · doi:10.1002/(sici)1097-4652(199910)181:1 · Cited by 32 · see citing works
Cloning and Characterization of the Human Protein Kinase C-η Promoter
Quan, T., & Fisher, G. J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.40.28566 · Cited by 27 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Molecular Mechanisms of Dermal Aging and Antiaging Approaches
Shin, J.-W., Kwon, S.-H., Choi, J.-Y., Na, J.-I., Huh, C.-H., Choi, H.-R., & Park, K.-C. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20092126 · Cited by 875 · see citing works
Fighting against Skin Aging: The Way from Bench to Bedside
Zhang, S., & Duan, E. (2018) · Cell Transplantation · doi:10.1177/0963689717725755 · Cited by 739 · see citing works
Quan, T., & Fisher, G. J. (2015) · Gerontology · doi:10.1159/000371708 · Cited by 464 · see citing works
Self-citationClinical aspects and molecular diagnostics of skin aging
Zouboulis, C. C., & Makrantonaki, E. (2011) · Clinics in Dermatology · doi:10.1016/j.clindermatol.2010.07.001 · Cited by 341 · see citing works
Zasada, M., & Budzisz, E. (2019) · Advances in Dermatology and Allergology · doi:10.5114/ada.2019.87443 · Cited by 315 · see citing works
The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence
Varesi, A., Chirumbolo, S., Campagnoli, L. I. M., Pierella, E., Piccini, G. B., Carrara, A., Ricevuti, G., Scassellati, C., Bonvicini, C., & Pascale, A. (2022) · Antioxidants · doi:10.3390/antiox11071224 · Cited by 145 · see citing works
Cell Autonomous and non-autonomous effects of senescent cells in the skin
Demaria, M., Desprez, P. Y., Campisi, J., & Velarde, M. C. (2015) · Journal of Investigative Dermatology · doi:10.1038/jid.2015.108 · Cited by 127 · see citing works
Molecular basis of retinol anti‐ageing properties in naturally aged human skin <i>in vivo</i>
Shao, Y., He, T., Fisher, G. J., Voorhees, J. J., & Quan, T. (2017) · International Journal of Cosmetic Science · doi:10.1111/ics.12348 · Cited by 130 · see citing works
Self-citationTreiber, N., Maity, P., Singh, K., Kohn, M., Keist, A. F., Ferchiu, F., Sante, L., Frese, S., Bloch, W., Kreppel, F., et al. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2010.00658.x · Cited by 109 · see citing works
Scarless wound healing: From development to senescence
Pratsinis, H., Mavrogonatou, E., & Kletsas, D. (2019) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.04.011 · Cited by 103 · see citing works
Vedrenne, N., Coulomb, B., Danigo, A., Bonté, F., & Desmoulière, A. (2012) · Pathologie Biologie · doi:10.1016/j.patbio.2011.10.002 · Cited by 89 · see citing works
Dermal Fibroblast CCN1 Expression in Mice Recapitulates Human Skin Dermal Aging
Quan, T., Xiang, Y., Liu, Y., Qin, Z., Yang, Y., Bou-Gharios, G., Voorhees, J. J., Dlugosz, A. A., & Fisher, G. J. (2021) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2020.07.019 · Cited by 30 · see citing works
Self-citationA high-throughput microphysiological system to quantify key events leading to liver fibrosis
Schmidt, S., & Suter-Dick, L. (2025) · Toxicology · doi:10.1016/j.tox.2025.154248 · Cited by 3 · see citing works
- Authors
- Quan, T., Shao, Y., He, T., Voorhees, J. J., & Fisher, G. J.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Fisher, Gary J.
- Venue
- Journal of Investigative Dermatology
- Publisher
- Elsevier BV
- Published
- 2010-02
- Volume
- 130
- Issue
- 2
- Pages
- 415-424
- ISSN
- 0022-202X (ISSN-L)
- PMC
- PMC2877594
- OpenAlex
- W2053402048
- Cited by
- 239
- References
- 57
- Citations by year
- 2026: 13 · 2025: 13 · 2024: 26 · 2023: 21 · 2022: 23 · 2021: 17 · 2020: 13 · 2019: 13 · 2018: 13 · 2017: 16 · 2016: 14 · 2015: 17 · 2014: 14 · 2013: 7 · 2012: 7
- FWCI
- 2.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Investigative Dermatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (AG019364, AG025186)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Health Sciences › Medicine › Dermatology › Skin Protection and Aging
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- connective tissue growth factor, skin aging, collagen loss, type I procollagen, TGF-β/Smad signaling, dermal fibroblasts, SMAD4, Smad7, Smad3, gene expression regulation, dermis
- MeSH terms
- Adult, Aged, Aged, 80 and over, Biopsy, Collagen, Fibroblasts, Fibrosis, Gene Expression Regulation, Humans, Middle Aged, Phosphorylation, Skin, Skin Physiological Phenomena, Skin Aging, Dermis, Connective Tissue Growth Factor
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
