Journal of Cell Communication and Signaling

, Volume 5, Issue 3, pp 201–207 | Cite as

CCN1 contributes to skin connective tissue aging by inducing age-associated secretory phenotype in human skin dermal fibroblasts

  • Taihao Quan
  • Zhaoping Qin
  • Patrick Robichaud
  • John J. Voorhees
  • Gary J. Fisher
Research Article


Dermal connective tissue collagen is the major structural protein in skin. Fibroblasts within the dermis are largely responsible for collagen production and turnover. We have previously reported that dermal fibroblasts, in aged human skin in vivo, express elevated levels of CCN1, and that CCN1 negatively regulates collagen homeostasis by suppressing collagen synthesis and increasing collagen degradation (Quan et al. Am J Pathol 169:482–90, 2006, J Invest Dermatol 130:1697–706, 2010). In further investigations of CCN1 actions, we find that CCN1 alters collagen homeostasis by promoting expression of specific secreted proteins, which include matrix metalloproteinases and proinflammatory cytokines. We also find that CCN1-induced secretory proteins are elevated in aged human skin in vivo. We propose that CCN1 induces an “Age-Associated Secretory Phenotype”, in dermal fibroblasts, which mediates collagen reduction and fragmentation in aged human skin.


CCN1 Age-associated secretory phenotype Skin connective tissue aging 



cysteine-rich protein 61

CCN family

cysteine-rich protein 61, connective tissue growth factor, nephroblastoma overexpressed


atomic force microscopy


matrix metalloproteinases


extracellular matrix


polymerase chain reaction




nuclear factor kappa B



We thank Suzan Rehbine for the procurement of tissue specimens, and Diane Fiolek for graphic and administrative assistance. This work was supported by the National Institute of Health (ES014697 and ES014697 30S1 to T Quan; AG019364 and AG025186 to G Fisher).


  1. Bai T, Chen CC, Lau LF (2010) Matricellular protein CCN1 activates a proinflammatory genetic program in murine macrophages. J Immunol 184:3223–3232PubMedCrossRefGoogle Scholar
  2. Bauge C, Legendre F, Leclercq S, Elissalde JM, Pujol JP, Galera P, Boumediene K (2007) Interleukin-1beta impairment of transforming growth factor beta1 signaling by down-regulation of transforming growth factor beta receptor type II and up-regulation of Smad7 in human articular chondrocytes. Arthritis Rheum 56:3020–3032PubMedCrossRefGoogle Scholar
  3. Cabodi S, del Pilar Camacho-Leal M, Di Stefano P, Defilippi P (2010) Integrin signalling adaptors: not only figurants in the cancer story. Nat Rev Cancer 10:858–870PubMedCrossRefGoogle Scholar
  4. Chang E, Goldberg H (1995) Requirements for transforming growth factor-beta regulation of the pro-alpha 2(I) collagen and plasminogen activator inhibitor-1 promoters. J Biol Chem 270:4473–4477PubMedCrossRefGoogle Scholar
  5. Chen CC, Lau LF (2009) Functions and mechanisms of action of CCN matricellular proteins. Int J Biochem Cell Biol 41:771–783PubMedCrossRefGoogle Scholar
  6. Chen SJ, Yuan W, Lo S, Trojanowska M, Varga J (2000) Interaction of smad3 with a proximal smad-binding element of the human alpha2(I) procollagen gene promoter required for transcriptional activation by TGF-beta. J Cell Physiol 183:381–392PubMedCrossRefGoogle Scholar
  7. Ershler WB, Sun WH, Binkley N, Gravenstein S, Volk MJ, Kamoske G, Klopp RG, Roecker EB, Daynes RA, Weindruch R (1993) Interleukin-6 and aging: blood levels and mononuclear cell production increase with advancing age and in vitro production is modifiable by dietary restriction. Lymphokine Cytokine Res 12:225–230PubMedGoogle Scholar
  8. Fisher GJ, Voorhees JJ (1998) Molecular mechanisms of photoaging and its prevention by retinoic acid: ultraviolet irradiation induces MAP kinase signal transduction cascades that induce Ap-1-regulated matrix metalloproteinases that degrade human skin in vivo. J Investig Dermatol Symp Proc 3:61–68PubMedCrossRefGoogle Scholar
  9. Fisher GJ, Henderson PA, Voorhees JJ, Baldassare JJ (1991) Epidermal growth factor-induced hydrolysis of phosphatidylcholine by phospholipase D and phospholipase C in human dermal fibroblasts. J Cell Physiol 146:309–317PubMedCrossRefGoogle Scholar
  10. Fisher GJ, Datta SC, Talwar HS, Wang ZQ, Varani J, Kang S, Voorhees JJ (1996) Molecular basis of sun-induced premature skin ageing and retinoid antagonism. Nature 379:335–339PubMedCrossRefGoogle Scholar
  11. Fisher GJ, Wang ZQ, Datta SC, Varani J, Kang S, Voorhees JJ (1997) Pathophysiology of premature skin aging induced by ultraviolet light. N Engl J Med 337:1419–1428PubMedCrossRefGoogle Scholar
  12. Fisher GJ, Talwar HS, Lin J, Lin P, McPhillips F, Wang Z, Li X, Wan Y, Kang S, Voorhees JJ (1998) Retinoic acid inhibits induction of c-Jun protein by ultraviolet radiation that occurs subsequent to activation of mitogen-activated protein kinase pathways in human skin in vivo. J Clin Invest 101:1432–1440PubMedCrossRefGoogle Scholar
  13. Fisher GJ, Kang S, Varani J, Bata-Csorgo Z, Wan Y, Datta S, Voorhees JJ (2002) Mechanisms of photoaging and chronological skin aging. Arch Dermatol 138:1462–1470PubMedCrossRefGoogle Scholar
  14. Fisher GJ, Quan T, Purohit T, Shao Y, Cho MK, He T, Varani J, Kang S, Voorhees JJ (2009) Collagen fragmentation promotes oxidative stress and elevates matrix metalloproteinase-1 in fibroblasts in aged human skin. Am J Pathol 174:101–114PubMedCrossRefGoogle Scholar
  15. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M et al (2007) Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128:92–105PubMedCrossRefGoogle Scholar
  16. Goto M (2008) Inflammaging (inflammation + aging): A driving force for human aging based on an evolutionarily antagonistic pleiotropy theory? Biosci Trends 2:218–230PubMedGoogle Scholar
  17. Hall MC, Young DA, Waters JG, Rowan AD, Chantry A, Edwards DR, Clark IM (2003) The comparative role of activator protein 1 and Smad factors in the regulation of Timp-1 and MMP-1 gene expression by transforming growth factor-beta 1. J Biol Chem 278:10304–10313PubMedCrossRefGoogle Scholar
  18. Ignotz RA, Massague J (1986) Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem 261:4337–4345PubMedGoogle Scholar
  19. Inagaki Y, Truter S, Ramirez F (1994) Transforming growth factor-beta stimulates alpha 2(I) collagen gene expression through a cis-acting element that contains an Sp1-binding site. J Biol Chem 269:14828–14834PubMedGoogle Scholar
  20. Jun JI, Lau LF (2010a) Cellular senescence controls fibrosis in wound healing. Aging (Albany NY) 2:627–631Google Scholar
  21. Jun JI, Lau LF (2010b) The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat Cell Biol 12:676–685PubMedCrossRefGoogle Scholar
  22. Kular L, Pakradouni J, Kitabgi P, Laurent M, Martinerie C (2011) The CCN family: a new class of inflammation modulators? Biochimie 93:377–388PubMedCrossRefGoogle Scholar
  23. Lau L, Lam SC-T (1999a) The CCN family of angiogenic regulators: The integrin connection. Exp Cell Res 248:44–57PubMedCrossRefGoogle Scholar
  24. Lau LF, Lam SC (1999b) The CCN family of angiogenic regulators: the integrin connection. Exp Cell Res 248:44–57PubMedCrossRefGoogle Scholar
  25. Leask A, Abraham DJ (2006) All in the CCN family: essential matricellular signaling modulators emerge from the bunker. J Cell Sci 119:4803–4810PubMedCrossRefGoogle Scholar
  26. Lencel P, Magne D (2011) Inflammaging: the driving force in osteoporosis? Med Hypotheses 76:317–321PubMedCrossRefGoogle Scholar
  27. Leu SJ, Lam SC, Lau LF (2002) Pro-angiogenic activities of CYR61 (CCN1) mediated through integrins alphavbeta3 and alpha6beta1 in human umbilical vein endothelial cells. J Biol Chem 277:46248–46255PubMedCrossRefGoogle Scholar
  28. Maggio M, Guralnik JM, Longo DL, Ferrucci L (2006) Interleukin-6 in aging and chronic disease: a magnificent pathway. J Gerontol A Biol Sci Med Sci 61:575–584PubMedGoogle Scholar
  29. Miranti CK, Brugge JS (2002) Sensing the environment: a historical perspective on integrin signal transduction. Nat Cell Biol 4:E83–E90PubMedCrossRefGoogle Scholar
  30. Monnier Y, Farmer P, Bieler G, Imaizumi N, Sengstag T, Alghisi GC, Stehle JC, Ciarloni L, Andrejevic-Blant S, Moeckli R et al (2008) CYR61 and alphaVbeta5 integrin cooperate to promote invasion and metastasis of tumors growing in preirradiated stroma. Cancer Res 68:7323–7331PubMedCrossRefGoogle Scholar
  31. Perbal B (2004) CCN proteins: multifunctional signalling regulators. Lancet 363:62–64PubMedCrossRefGoogle Scholar
  32. Quan T, He T, Kang S, Voorhees JJ, Fisher GJ (2002) Connective tissue growth factor: expression in human skin in vivo and inhibition by ultraviolet irradiation. J Invest Dermatol 118:402–408PubMedCrossRefGoogle Scholar
  33. Quan T, He T, Kang S, Voorhees JJ, Fisher GJ (2004) Solar ultraviolet irradiation reduces collagen in photoaged human skin by blocking transforming growth factor-beta type II receptor/Smad signaling. Am J Pathol 165:741–751PubMedCrossRefGoogle Scholar
  34. Quan T, He T, Shao Y, Lin L, Kang S, Voorhees JJ, Fisher GJ (2006) Elevated cysteine-rich 61 mediates aberrant collagen homeostasis in chronologically aged and photoaged human skin. Am J Pathol 169:482–490PubMedCrossRefGoogle Scholar
  35. Quan T, Qin Z, Xu Y, He T, Kang S, Voorhees JJ, Fisher GJ (2010) Ultraviolet irradiation induces CYR61/CCN1, a mediator of collagen homeostasis, through activation of transcription factor AP-1 in human skin fibroblasts. J Invest Dermatol 130:1697–1706PubMedCrossRefGoogle Scholar
  36. Quan T, Qin Z, Shao Y, Xu Y, Voorhees JJ, Fisher GJ (2011) Retinoids suppress cysteine-rich protein 61 (CCN1), a negative regulator of collagen homeostasis, in skin equivalent cultures and aged human skin in vivo. Exp DermatolGoogle Scholar
  37. Schober JM, Lau LF, Ugarova TP, Lam SC (2003) Identification of a novel integrin alphaMbeta2 binding site in CCN1 (CYR61), a matricellular protein expressed in healing wounds and atherosclerotic lesions. J Biol Chem 278:25808–25815PubMedCrossRefGoogle Scholar
  38. Singh T, Newman AB (2011) Inflammatory markers in population studies of aging. Ageing Res Rev 10:319–329PubMedCrossRefGoogle Scholar
  39. Stupack DG, Cheresh DA (2002) Get a ligand, get a life: integrins, signaling and cell survival. J Cell Sci 115:3729–3738PubMedCrossRefGoogle Scholar
  40. Svineng G, Ravuri C, Rikardsen O, Huseby NE, Winberg JO (2008) The role of reactive oxygen species in integrin and matrix metalloproteinase expression and function. Connect Tissue Res 49:197–202PubMedCrossRefGoogle Scholar
  41. Varani J, Warner RL, Gharaee-Kermani M, Phan SH, Kang S, Chung JH, Wang ZQ, Datta SC, Fisher GJ, Voorhees JJ (2000) Vitamin A antagonizes decreased cell growth and elevated collagen-degrading matrix metalloproteinases and stimulates collagen accumulation in naturally aged human skin. J Invest Dermatol 114:480–486PubMedCrossRefGoogle Scholar
  42. 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 168:1861–1868PubMedCrossRefGoogle Scholar
  43. Vincenti MP, Brinckerhoff CE (2002) Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: integration of complex signaling pathways for the recruitment of gene-specific transcription factors. Arthritis Res 4:157–164PubMedCrossRefGoogle Scholar
  44. Westermarck J, Li SP, Kallunki T, Han J, Kahari VM (2001) p38 mitogen-activated protein kinase-dependent activation of protein phosphatases 1 and 2A inhibits MEK1 and MEK2 activity and collagenase 1 (MMP-1) gene expression. Mol Cell Biol 21:2373–2383PubMedCrossRefGoogle Scholar
  45. White LA, Mitchell TI, Brinckerhoff CE (2000) Transforming growth factor beta inhibitory element in the rabbit matrix metalloproteinase-1 (collagenase-1) gene functions as a repressor of constitutive transcription. Biochim Biophys Acta 1490:259–268PubMedGoogle Scholar
  46. Wlaschek M, Heinen G, Poswig A, Schwarz A, Krieg T, Scharffetter-Kochanek K (1994) UVA-induced autocrine stimulation of fibroblast-derived collagenase/MMP-1 by interrelated loops of interleukin-1 and interleukin-6. Photochem Photobiol 59:550–556PubMedCrossRefGoogle Scholar

Copyright information

© The International CCN Society 2011

Authors and Affiliations

  • Taihao Quan
    • 1
  • Zhaoping Qin
    • 1
  • Patrick Robichaud
    • 1
  • John J. Voorhees
    • 1
  • Gary J. Fisher
    • 1
  1. 1.Department of DermatologyUniversity of Michigan Medical SchoolAnn ArborUSA

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