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Expression and regulation of intracellular SMAD signaling in scleroderma skin fibroblasts

  1. Yasuji Mori,
  2. Shu-Jen Chen,
  3. John Varga*

Article first published online: 2 JUL 2003

DOI: 10.1002/art.11157

Issue

Arthritis & Rheumatism

Arthritis & Rheumatism

Volume 48, Issue 7, pages 1964–1978, July 2003

Additional Information

How to Cite

Mori, Y., Chen, S.-J. and Varga, J. (2003), Expression and regulation of intracellular SMAD signaling in scleroderma skin fibroblasts. Arthritis & Rheumatism, 48: 1964–1978. doi: 10.1002/art.11157

Author Information

  1. University of Illinois at Chicago College of Medicine

*Section of Rheumatology (M/C 733), University of Illinois College of Medicine, Room 1158 Molecular Biology Research Building, 900 South Ashland Avenue, Chicago, IL 60607

Publication History

  1. Issue published online: 2 JUL 2003
  2. Article first published online: 2 JUL 2003
  3. Manuscript Accepted: 12 MAR 2003
  4. Manuscript Received: 28 OCT 2002

Funded by

  • NIH. Grant Number: AR-42309
  • Scleroderma Foundation

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REFERENCES

  • 1
    Varga J, Mori Y, Takagawa S. Molecular and cellular basis of fibrosis. Semin Clin Immunol 2000; 2: 15–29.
  • 2
    Widom RL. Regulation of matrix biosynthesis and degradation in systemic sclerosis. Curr Opin Rheumatol 2000; 12: 534–9.
  • 3
    Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor beta in human disease. N Engl J Med 2000; 342: 1350–8.
  • 4
    Kulozik M, Hogg A, Lankat-Buttgereit B, Krieg T. Co-localization of transforming growth factor beta 2 with alpha 1(I) procollagen mRNA in tissue sections of patients with systemic sclerosis. J Clin Invest 1990; 86: 917–22.
  • 5
    Gabrielli A, Di Loreto C, Taborro R, Candela M, Sambo P, Nitti C, et al. Immunohistochemical localization of intracellular and extracellular associated TGF beta in the skin of patients with systemic sclerosis (scleroderma) and primary Raynaud's phenomenon. Clin Immunol Immunopathol 1993; 68: 340–9.
  • 6
    Gruschwitz M, Muller PU, Sepp N, Hofer E, Fontana A, Wick G. Transcription and expression of transforming growth factor type beta in the skin of progressive systemic sclerosis: a mediator of fibrosis? J Invest Dermatol 1990; 94: 197–203.
  • 7
    Sfikakis PP, McCune BK, Tsokos M, Aroni K, Vayiopoulos G, Tsokos GC. Immunohistological demonstration of transforming growth factor-beta isoforms in the skin of patients with systemic sclerosis. Clin Immunol Immunopathol 1993; 69: 199–204.
  • 8
    Rudnicka L, Varga J, Christiano AM, Iozzo RV, Jimenez SA, Uitto J. Elevated expression of type VII collagen in the skin of patients with systemic sclerosis: regulation by transforming growth factor-beta. J Clin Invest 1996; 93: 1709–15.
  • 9
    Mason GI, Hamburger J, Matthews JB. Mast cells, extracellular matrix components, TGFβ isoforms and TGFβ receptor expression in labial salivary glands in systemic sclerosis. Ann Rheum Dis 2000; 59: 183–9.
  • 10
    Higley H, Persichitte K, Chu S, Waegell W, Vancheeswaran R, Black C. Immunocytochemical localization and serologic detection of transforming growth factor β1: association with type I procollagen and inflammatory cell markers in diffuse and limited systemic sclerosis, morphea, and Raynaud's phenomenon. Arthritis Rheum 1994; 37: 278–88.
    Direct Link:
  • 11
    Querfeld C, Eckes B, Huerkamp C, Krieg T, Sollberg S. Expression of TGF-beta 1, -beta 2 and -beta 3 in localized and systemic scleroderma. J Dermatol Sci 1999; 21: 13–22.
  • 12
    Kawakami T, Ihn H, Xu W, Smith E, LeRoy C, Trojanowska M. Increased expression of TGF-beta receptors by scleroderma fibroblasts: evidence for contribution of autocrine TGF-beta signaling to scleroderma phenotype. J Invest Dermatol 1998; 110: 47–51.
  • 13
    Ihn H, Yamane K, Kubo M, Tamaki K. Blockade of endogenous transforming growth factor β signaling prevents up-regulated collagen synthesis in scleroderma fibroblasts: association with increased expression of transforming growth factor β receptors. Arthritis Rheum 2001; 44: 474–80.
    Direct Link:
  • 14
    Kubo M, Ihn H, Yamane K, Tamaki K. Up-regulated expression of transforming growth factor β receptors in dermal fibroblasts in skin sections from patients with localized scleroderma. Arthritis Rheum 2001; 44: 731–4.
    Direct Link:
  • 15
    McCormick LL, Zhang Y, Tootell E, Gilliam AC. Anti-TGF-beta treatment prevents skin and lung fibrosis in murine sclerodermatous graft-versus-host disease: a model for human scleroderma. J Immunol 1999; 163: 5693–9.
  • 16
    Yamamoto T, Takagawa S, Katayama I, Nishioka K. Anti-sclerotic effect of transforming growth factor-beta antibody in a mouse model of bleomycin-induced scleroderma. Clin Immunol 1999; 92: 6–13.
  • 17
    McGaha T, Saito S, Phelps RG, Gordon R, Noben-Trauth N, Paul WE, et al. Lack of skin fibrosis in tight skin (TSK) mice with targeted mutation in the interleukin-4R alpha and transforming growth factor-beta genes. J Invest Dermatol 2001; 116: 136–43.
  • 18
    Verrecchia F, Chu ML, Mauviel A. Identification of novel TGF-beta/Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach. J Biol Chem 2001; 276: 17058–62.
  • 19
    Van Obberghen-Schilling E, Roche NS, Flanders KC, Sporn MB, Roberts AB. Transforming growth factor beta 1 positively regulates its own expression in normal and transformed cells. J Biol Chem 1988; 263: 7741–6.
  • 20
    Grotendorst GR, Okochi H, Hayashi N. A novel transforming growth factor beta response element controls the expression of the connective tissue growth factor gene. Cell Growth Differ 1996; 7: 469–80.
  • 21
    Massague J, Wotton D. Transcriptional control by the TGF-beta/Smad signaling system. EMBO J 2000; 19: 1745–54.
  • 22
    Topper JN, Cai J, Qiu Y, Anderson KR, Xu YY, Deeds JD, et al. Vascular MADs: two novel MAD-related genes selectively inducible by flow in human vascular endothelium. Proc Natl Acad Sci U S A 1997; 94: 9314–9.
  • 23
    Nakao A, Afrakhte M, Moren A, Nakayama T, Christian JL, Heuchel R, et al. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature 1997; 389: 631–5.
  • 24
    Mori Y, Chen SJ, Varga J. Modulation of endogenous Smad expression in normal skin fibroblasts by transforming growth factor-beta. Exp Cell Res 2000; 258: 374–83.
  • 25
    Moustakas A, Souchelnytskyi S, Heldin CH. Smad regulation in TGF-beta signal transduction. J Cell Sci 2001; 114: 4359–69.
  • 26
    Tsukazaki T, Chiang TA, Davison AF, Attisano L, Wrana JL. SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor. Cell 1998; 95: 779–91.
  • 27
    Dong C, Li Z, Alvarez R Jr, Feng XH, Goldschmidt-Clermont PJ. Microtubule binding to Smads may regulate TGF beta activity. Mol Cell 2000; 5: 27–34.
  • 28
    Lo RS, Massague J. Ubiquitin-dependent degradation of TGF-beta-activated Smad2. Nat Cell Biol 1999; 1: 472–8.
  • 29
    Chen SJ, Yuan W, Mori Y, Levenson A, Trojanowska M, Varga J. Stimulation of type I collagen transcription in human skin fibroblasts by TGF-beta: involvement of Smad 3. J Invest Dermatol 1999; 112: 49–57.
  • 30
    Chen SJ, Yuan W, Lo S, Trojanowska M, Varga J. 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 2000; 183: 381–92.
    Direct Link:
  • 31
    Ghosh AK, Yuan W, Mori Y, Varga J. Smad-dependent stimulation of type I collagen gene expression in human skin fibroblasts by TGF-beta involves functional cooperation with p300/CBP transcriptional coactivators. Oncogene 2000; 19: 3546–55.
  • 32
    Poncelet AC, Schnaper HW. Sp1 and Smad proteins cooperate to mediate TGF-beta1-induced alpha2(I) collagen expression in human glomerular mesangial cells. J Biol Chem 2001; 276: 6983–92.
  • 33
    Zhang W, Ou J, Inagaki Y, Greenwel P, Ramirez F. Synergistic cooperation between Sp1 and Smad3/Smad4 mediates transforming growth factor beta1 stimulation of alpha 2(I) collagen (COL1A2) transcription. J Biol Chem 2000; 275: 39237–45.
  • 34
    Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980; 23: 581–90.
    Direct Link:
  • 35
    Brand T, MacLellan WR, Schneider MD. A dominant-negative receptor for type beta transforming growth factors created by deletion of the kinase domain. J Biol Chem 1993; 268: 11500–3.
  • 36
    Zawel L, Dai JL, Buckhaults P, Zhou S, Kinzler KW, Vogelstein B, et al. Human Smad3 and Smad4 are sequence-specific transcription activators. Mol Cell 1998; 1: 611–7.
  • 37
    Wakefield LM, Roberts AB. TGF-beta signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev 2002; 12: 22–9.
  • 38
    Ghosh AK, Yuan W, Mori Y, Chen S, Varga J. Antagonistic regulation of type I collagen gene expression by interferon-gamma and transforming growth factor-beta: integration at the level of p300/CBP transcriptional coactivators. J Biol Chem 2001; 276: 11041–8.
  • 39
    Varga J. Scleroderma and Smads: dysfunctional Smad family dynamics culminating in fibrosis. Arthritis Rheum 2002; 46: 1703–13.
    Direct Link:
  • 40
    Holmes A, Abraham DJ, Sa S, Shiwen X, Black CM, Leask A. CTGF and Smads, maintenance of scleroderma phenotype is independent of Smad signaling. J Biol Chem 2001; 276: 10594–601.
  • 41
    Piek E, Ju WJ, Heyer J, Escalante-Alcalde D, Stewart CL, Weinstein M, et al. Functional characterization of transforming growth factor beta signaling in Smad2- and Smad3-deficient fibroblasts. J Biol Chem 2001; 276: 19945–53.
  • 42
    Roberts AB, Piek E, Bottinger EP, Ashcroft G, Mitchell JB, Flanders KC. Is Smad3 a major player in signal transduction pathways leading to fibrogenesis? Chest 2001; 120: 43S–47S.
  • 43
    Dooley S, Streckert M, Delvoux B, Gressner AM. Expression of Smads during in vitro transdifferentiation of hepatic stellate cells to myofibroblasts. Biochem Biophys Res Commun 2001; 283: 554–62.
  • 44
    Hong S, Isono M, Chen S, Iglesias-De La Cruz MC, Han DC, Ziyadeh FN. Increased glomerular and tubular expression of transforming growth factor-beta1, its type II receptor, and activation of the Smad signaling pathway in the db/db mouse. Am J Pathol 2001; 158: 1653–63.
  • 45
    Yanagisawa K, Osada H, Masuda A, Kondo M, Saito T, Yatabe Y, et al. Induction of apoptosis by Smad3 and down-regulation of Smad3 expression in response to TGF-beta in human normal lung epithelial cells. Oncogene 1998; 17: 1743–7.
  • 46
    Poncelet AC, de Caestecker MP, Schnaper HW. The transforming growth factor-beta/SMAD signaling pathway is present and functional in human mesangial cells. Kidney Int 1999; 56: 1354–65.
  • 47
    Zhao Y, Geverd DA. Regulation of Smad3 expression in bleomycin-induced pulmonary fibrosis: a negative feedback loop of TGF-beta signaling. Biochem Biophys Res Commun 2002; 294: 319–23.
  • 48
    Bitzer M, von Gersdorff G, Liang D, Dominguez-Rosales A, Beg AA, Rojkind M, et al. A mechanism of suppression of TGF-beta/SMAD signaling by NF-kappa B/RelA. Genes Dev 2000; 14: 187–97.
  • 49
    Tahashi Y, Matsuzaki K, Date M, Yoshida K, Furukawa F, Sugano Y, et al. Differential regulation of TGF-beta signal in hepatic stellate cells between acute and chronic rat liver injury. Hepatology 2002; 35: 49–61.
    Direct Link:
  • 50
    Dooley S, Delvoux B, Lahme B, Mangasser-Stephan K, Gressner AM. Modulation of transforming growth factor beta response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts. Hepatology 2000; 31: 1094–106.
    Direct Link:
  • 51
    Uchida K, Nitta K, Kobayashi H, Kawachi H, Shimizu F, Yumura W, et al. Localization of Smad6 and Smad7 in the rat kidney and their regulated expression in the anti-Thy-1 nephritis. Mol Cell Biol Res Commun 2000; 4: 98–105.
  • 52
    Schiffer M, Bitzer M, Roberts IS, Kopp JB, ten Dijke P, Mundel P, et al. Apoptosis in podocytes induced by TGF-beta and Smad7. J Clin Invest 2001; 108: 807–16.
  • 53
    Dong C, Zhu S, Wang T, Yoon W, Li Z, Alvarez RJ, et al. Deficient Smad7 expression: a putative molecular defect in scleroderma. Proc Natl Acad Sci U S A 2002; 99: 3908–13.
  • 54
    Xiao Z, Liu X, Henis YI, Lodish HF. A distinct nuclear localization signal in the N terminus of Smad 3 determines its ligand-induced nuclear translocation. Proc Natl Acad Sci U S A 2000; 97: 7853–5.
  • 55
    Liu F, Pouponnot C, Massague J. Dual role of the Smad4/DPC4 tumor suppressor in TGF-beta-inducible transcriptional complexes. Genes Dev 1997; 11: 3157–67.
  • 56
    Inagaki Y, Mamura M, Kanamaru Y, Greenwel P, Nemoto T, Takehara K, et al. Constitutive phosphorylation and nuclear localization of Smad3 are correlated with increased collagen gene transcription in activated hepatic stellate cells. J Cell Physiol 2001; 187: 117–23.
    Direct Link:
  • 57
    Chin GS, Liu W, Peled Z, Lee TY, Steinbrech DS, Hsu M, et al. Differential expression of transforming growth factor-beta receptors I and II and activation of Smad 3 in keloid fibroblasts. Plast Reconstr Surg 2001; 108: 423–9.
  • 58
    Yuan W, Varga J. Transforming growth factor-beta repression of matrix metalloproteinase-1 in dermal fibroblasts involves Smad3. J Biol Chem 2001; 276: 38502–10.
  • 59
    Takeda K, Hatamochi A, Ueki H, Nakata M, Oishi Y. Decreased collagenase expression in cultured systemic sclerosis fibroblasts. J Invest Dermatol 1994; 103: 359–63.
  • 60
    Ihn H, Tamaki K. Increased phosphorylation of transcription factor Sp1 in scleroderma fibroblasts: association with increased expression of the type I collagen gene. Arthritis Rheum 2000; 43: 2240–7.
    Direct Link:
  • 61
    Inman GJ, Nicolas FJ, Hill CS. Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity. Mol Cell 2002; 10: 283–94.
  • 62
    Leask A, Abraham DJ, Finlay DR, Holmes A, Pennington D, Shi-Wen X, et al. Dysregulation of transforming growth factor β signaling in scleroderma: overexpression of endoglin in cutaneous scleroderma fibroblasts. Arthritis Rheum 2002; 46: 1857–65.
    Direct Link:
  • 63
    Fanayan S, Firth SM, Baxter RC. Signaling through the Smad pathway by insulin-like growth factor binding protein-3 in breast cancer cells: relationship to transforming growth factor-1 signaling. J Biol Chem 2002; 277: 7255–61.
  • 64
    Feghali CA, Wright TM. Identification of multiple, differentially expressed messenger RNAs in dermal fibroblasts from patients with systemic sclerosis. Arthritis Rheum 1999; 42: 1451–7.
    Direct Link:
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