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Antifibrotic therapy in scleroderma: Extracellular or intracellular targeting of activated fibroblasts?

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Abstract

Therapeutic anticytokine approaches have revolutionized the treatment of chronic inflammatory diseases, and targeting of transforming growth factor-beta (TGF-β), a key factor in the pathogenesis of fibrosis, is undergoing evaluation for scleroderma. Several considerations dictate a cautious approach to anti-TGF-β interventions. These include the possibility of multiple cytokines having overlapping roles in the pathogenesis of fibrosis and concerns that, in light of its numerous homeostatic functions, blocking TGF-β may have serious adverse consequences. Furthermore, as autonomously activated cells, scleroderma fibroblasts may be unresponsive to blockade of TGF-β signaling. This article reviews the experimental evidence underlying these concerns, and indicates rational approaches to addressing and overcoming them.

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References and Recommended Reading

  1. Blobe GC, Schiemann WP, Lodish HF: Role of transforming growth factor beta in human disease. N Engl J Med 2000, 342:1350–1358.

    Article  PubMed  CAS  Google Scholar 

  2. Trojanowska M: Molecular aspects of scleroderma. Front Biosci 2002, 7:608–618.

    Article  Google Scholar 

  3. Chambers RC, Leoni P, Kaminski N, et al.: Global expression profiling of fibroblast responses to transforming growth factor-beta1 reveals the induction of inhibitor of differentiation- 1 and provides evidence of smooth muscle cell phenotypic switching. Am J Pathol 2003, 162:533–546. This study examined global patterns of TGF-β-regulated gene expression in fibroblasts. The results showed that many of the genes whose expression was upregulated by TGF-β encoded extracellular matrix proteins, myofibroblast markers, or other proteins that are known to play roles in fibrogenesis, consistent with the notion that TGF-β plays a key role in the pathogenesis of tissue fibrosis.

    PubMed  CAS  Google Scholar 

  4. Yamamoto T, Nishioka K: Role of monocyte chemoattractant protein-1 and its receptor, CCR-2, in the pathogenesis of bleomycin-induced scleroderma. J Invest Dermatol 2003, 121:510–516.

    Article  PubMed  CAS  Google Scholar 

  5. Distler O, Pap T, Kowal-Bielecka O, et al.: Overexpression of monocyte chemoattractant protein 1 in systemic sclerosis: role of platelet-derived growth factor and effects on monocyte chemotaxis and collagen synthesis. Arthritis Rheum 2001, 44:2665–2278.

    Article  PubMed  CAS  Google Scholar 

  6. Holmes A, Abraham DJ, Sa S, et al.: CTGF and SMADs, maintenance of scleroderma phenotype is independent of SMAD signaling. J Biol Chem 2001, 276:10594–10560.

    Article  PubMed  CAS  Google Scholar 

  7. Keffer J, Probert L, Cazlaris H, et al.: Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J 1991, 10:4025–4031.

    PubMed  CAS  Google Scholar 

  8. Andreakos ET, Foxwell BM, Brennan FM, et al.: Cytokines and anti-cytokine biologicals in autoimmunity: present and future. Cytokine Growth Factor Rev 2002, 13:299–313.

    Article  PubMed  CAS  Google Scholar 

  9. Elliott MJ, Maini RN, Feldmann M, et al.: Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum 1993, 36:1681–1690.

    Article  PubMed  CAS  Google Scholar 

  10. Redlich K, Schett G, Steiner G, et al.: Rheumatoid arthritis therapy after tumor necrosis factor and interleukin-1 blockade. Arthritis Rheum 2003, 48:3308–3319.

    Article  PubMed  CAS  Google Scholar 

  11. Varga J: Scleroderma and Smads: dysfunctional Smad family dynamics culminating in fibrosis. Arthritis Rheum 2002, 46:1703–1713.

    Article  PubMed  CAS  Google Scholar 

  12. 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.

    Article  PubMed  CAS  Google Scholar 

  13. 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, 163:5693–5699.

    PubMed  CAS  Google Scholar 

  14. Kulkarni AB, Huh CG, Becker D, et al.: Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci U S A. 1993, 90:770–774.

    Article  PubMed  CAS  Google Scholar 

  15. Shull MM, Ormsby I, Kier AB, et al.: Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 1992, 359:693–699.

    Article  PubMed  CAS  Google Scholar 

  16. Diebold RJ, Eis MJ, Yin M, et al.: Early-onset multifocal inflammation in the transforming growth factor beta 1-null mouse is lymphocyte mediated. Proc Natl Acad Sci U S A 1995, 92:12215–12219.

    Article  PubMed  CAS  Google Scholar 

  17. Chen W, Wahl SM: TGF-beta: receptors, signaling pathways and autoimmunity. Curr Dir Autoimmun 2002, 5:62–91.

    Article  PubMed  CAS  Google Scholar 

  18. O’Kane S, Ferguson MWJ: Transforming growth factor ß and wound healing. Int J Biochem Cell Biol 1997, 29:63–78.

    Article  PubMed  CAS  Google Scholar 

  19. Reiss M: TGF-beta and cancer. Microbes Infect 1999, 1:1327–1347.

    Article  PubMed  CAS  Google Scholar 

  20. Pierce DF, Jr., Gorska AE, Chytil A, et al.: Mammary tumor suppression by transforming growth factor beta 1 transgene expression. Proc Natl Acad Sci U S A 1995, 92:4254–4258.

    Article  PubMed  CAS  Google Scholar 

  21. Tang B, Bottinger EP, Jakowlew SB, et al.: Transforming growth factor-beta1 is a new form of tumor suppressor with true haploid insufficiency. Nat Med 1998, 4:802–807.

    Article  PubMed  CAS  Google Scholar 

  22. Grainger DJ: Transforming growth factor-beta and atherosclerosis: so far, so good for the protective cytokine hypothesis. Arterioscler Thromb Vasc Biol 2003, in press.

  23. Andreotti F, Porto I, Crea F, Maseri A: Inflammatory gene polymorphisms and ischemic heart disease: review of population association studies. Heart 2002, 87:107–112.

    Article  PubMed  CAS  Google Scholar 

  24. Grainger DJ, Kemp PR, Metcalfe JC, et al.: The serum concentration of active transforming growth factor-beta is severely depressed in advanced atherosclerosis. Nat Med 1995, 1:74–79.

    Article  PubMed  CAS  Google Scholar 

  25. Mallat Z, Gojova A, Marchiol-Fournigault C, et al.: Inhibition of transforming growth factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice. Circ Res 2001, 89:930–934.

    PubMed  CAS  Google Scholar 

  26. Robertson AK, Rudling M, Zhou X, et al.: Disruption of TGFbeta signaling in T cells accelerates atherosclerosis. J Clin Invest 2003, 112:1342–1350.

    Article  PubMed  CAS  Google Scholar 

  27. 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, 43:2240–2247.

    Article  PubMed  CAS  Google Scholar 

  28. Chen SJ, Takagawa S, Mori Y, Varga J: Egr-1, a potential regulator of fibrosis, is upregulated by Smad3 and TGF-beta, and in bleomycin-treated mice and scleroderma patients [abstract]. Arthritis Rheum 2003, 48:S668.

    Article  CAS  Google Scholar 

  29. Mori Y, Chen SJ, Varga J: Expression and regulation of intracellular SMAD signaling in scleroderma skin fibroblasts. Arthritis Rheum 2003, 48:1964–1978. This study exhaustively characterized the expression, activation, and cellular distribution of Smads in human scleroderma fibroblasts. The results showed that Smads displayed a ligand-independent activation and nuclear accumulation of Smads that could not be reversed by blocking TGF-β signaling. These abnormalities may contribute to the activated phenotype of scleroderma fibroblasts.

    Article  PubMed  CAS  Google Scholar 

  30. Kubo M, Czuwara-Ladykowska J, Moussa O, et al.: Persistent down-regulation of Fli1, a suppressor of collagen transcription, in fibrotic scleroderma skin. Am J Pathol 2003, 163:571–581. In this study, fibroblasts in lesional scleroderma skin were shown to have reduced expression levels of the transcription factor Fli-1, a transcriptional repressor of collagen gene expression. The authors suggest that impaired negative regulation of collagen production may contribute to fibrosis.

    PubMed  CAS  Google Scholar 

  31. Dong C, Zhu S, Wang T, et al.: Deficient Smad7 expression: a putative molecular defect in scleroderma. Proc Natl Acad Sci U S A 2002, 99:3908–3913.

    Article  PubMed  CAS  Google Scholar 

  32. Cicchillitti L, Jimenez SA, Sala A, Saitta B: B-Myb acts as a repressor of human COL1A1 collagen gene expression by interacting with Sp1 and CBF factors in scleroderma fibroblasts. Biochem J 2003, in press.

  33. Leask A, Abraham DJ, Finlay DR, et al.: Dysregulation of transforming growth factor beta signaling in scleroderma: overexpression of endoglin in cutaneous scleroderma fibroblasts. Arthritis Rheum 2002, 46:1857–1865.

    Article  PubMed  CAS  Google Scholar 

  34. Yamane K, Ihn H, Kubo M, Tamaki K: Increased transcriptional activities of transforming growth factor beta receptors in scleroderma fibroblasts. Arthritis Rheum 2002, 46:2421–2428. This study demonstrated that lesional scleroderma fibroblasts display elevated levels for the membrane receptors for TGF-β, suggesting that autocrine TGF-β stimulation may play a role in their autonomous activation.

    Article  PubMed  CAS  Google Scholar 

  35. Hu B, Wang S, Zhang Y, et al.: A nuclear target for interleukin- 1alpha: interaction with the growth suppressor necdin modulates proliferation and collagen expression. Proc Natl Acad Sci U S A 2003, 100:10008–10013. This innovative study showed that in scleroderma fibroblasts, the inflammatory cytokine interleukin-alpha was overexpressed and localized within the nucleus. This observation points to a potential role for interleukin-alpha in an "intracrine" stimulatory loop.

    Article  PubMed  CAS  Google Scholar 

  36. Lakos G, Takagawa S, Varga J: Lack of Smad3 modulates the development of dermal fibrosis in bleomycin-induced murine scleroderma [abstract]. Arthritis Rheum 2003, 48:S155.

    Google Scholar 

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

    John Varga MD

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  1. John Varga MD
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Varga, J. Antifibrotic therapy in scleroderma: Extracellular or intracellular targeting of activated fibroblasts?. Curr Rheumatol Rep 6, 164–170 (2004). https://doi.org/10.1007/s11926-004-0062-8

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  • DOI: https://doi.org/10.1007/s11926-004-0062-8

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