Systemic sclerosis: A prototypic multisystem fibrotic disorder

Journal of Clinical Investigation

Volumn 117, Issue 3, 2007, Pages 557-567

  Varga, John ^a   Abraham, David ^b  

^a NORTHWESTERN UNIVERSITY   (United States)

^b UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

IMMUNOMODULATING AGENT;

AUTOIMMUNITY; FIBROSIS; IMMUNOMODULATION; MORBIDITY; MORTALITY; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; SYSTEMIC SCLEROSIS; VASCULAR DISEASE;

ANIMALS; AUTOIMMUNITY; BLOOD VESSELS; DISEASE MODELS, ANIMAL; FIBROSIS; SCLERODERMA, SYSTEMIC;

EID: 33847348491     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI31139     Document Type: Review

References (123)

1. Abraham, D.J., and Varga, J. 2005. Scleroderma: from cell and molecular mechanisms to disease models. Trends Immunol. 26:587-595.
2. LeRoy, E.C., and Medsger, T.A., Jr. 2001. Criteria for the classification of early systemic sclerosis. J. Rheumatol. 28:1573-1576.
3. Mayes, M.D., et al. 2003. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 48:2246-2255.
4. Feghali-Bostwick, C., Medsger, T.A., Jr., and Wright, T.M. 2003. Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Arthritis Rheum. 48:1956-1963.
5. Arnett, F.C., et al. 2001. Familial occurrence frequencies and relative risks for systemic sclerosis (scleroderma) in three United States cohorts. Arthritis Rheum. 44:1359-1362.
6. Pandey, J.P., and LeRoy, E.C. 1998. Human cytomegalovirus and the vasculopathies of autoimmune diseases (especially scleroderma), allograft rejection, and coronary restenosis. Arthritis Rheum. 41:10-15.
7. Nietert, P.J., and Silver, R.M. 2000. Systemic sclerosis: environmental and occupational risk factors. Curr. Opin. Rheumatol. 12:520-526.
8. Namboodiri, A.M., Rocca, K.M., and Pandey, J.P. 2004. IgG antibodies to human cytomegalovirus late protein UL94 in patients with systemic sclerosis. Autoimmunity. 37:241-244.
9. Lunardi, C., et al. 2006. Antibodies against human cytomegalovirus in the pathogenesis of systemic sclerosis: a gene array approach. PLoS Med. 3:e2.
10. Lunardi, C., et al. 2000. Systemic sclerosis immunoglobulin G autoantibodies bind the human cytomegalovirus late protein UL94 and induce apoptosis in human endothelial cells. Nat. Med. 6:1183-1186.
11. Inkinen, K., et al. 2005. Cytomegalovirus enhance expression of growth factors during the development of chronic allograft nephropathy in rats. Transpl. Int. 18:743-749.
12. Green, M.C., Sweet, H.O., and Bunker, L.E. 1976. Tight-skin, a new mutation of the mouse causing excessive growth of connective tissue and skeleton. Am. J. Pathol. 82:493-512.
13. Baxter, R.M., Crowell, T.P., McCrann, M.E., Frew, E.M., and Gardner, H. 2005. Analysis of the tight skin (Tsk1/+) mouse as a model for testing antifibrotic agents. Lab. Invest. 85:1199-1209.
14. Siracusa, L.D., et al. 1996. A tandem duplication within the fibrillin 1 gene is associated with the mouse tight skin mutation. Genome Res. 6:300-313.
15. Habashi, J.P., et al. 2006. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 312:117-121.
16. Isogai, Z., et al. 2003. Latent transforming growth factor-beta-binding protein 1 interacts with fibrillin and is a microfibril-associated protein. J. Biol. Chem. 278:2750-2757.
17. Yamamoto, T., et al. 1999. Animal model of sclerotic skin. I: Local injections of bleomycin induce sclerotic skin mimicking scleroderma. J. Invest. Dermatol. 112:456-462.
18. Takagawa, S., et al. 2003. Sustained activation of fibroblast transforming growth factor-beta/Smad signaling in a murine model of SSc. J. Invest. Dermatol. 121:41-50.
19. Lakos, G., et al. 2004. Targeted disruption of TGF-beta/Smad3 signaling modulates skin fibrosis in a mouse model of scleroderma. Am. J. Pathol. 165:203-217.
20. Ferreira, A.M., et al. 2006. Diminished induction of skin fibrosis in mice with MCP-1 deficiency. J. Invest. Dermatol. 126:1900-1908.
21. Zhang, Y., McCormick, L.L., Desai, S.R., Wu, C., and Gilliam, A.C. 2002. Murine sclerodermatous graft-versus-host disease, a model for human scleroderma: cutaneous cytokines, chemokines, and immune cell activation. J. Immunol. 168:3088-3098.
22. Ruzek, M.C., Jha, S., Ledbetter, S., Richards, S.M., and Garman, R.D. 2004. A modified model of graft-versus-host-induced systemic sclerosis (scleroderma) exhibits all major aspects of the human disease. Arthritis Rheum. 50:1319-1331.
23. Samuel, C.S., et al. 2005. The relaxin gene knockout mouse: a model of progressive scleroderma. J. Invest. Dermatol. 125:692-699.
24. Razani, B., et al. 2001. Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities. J. Biol. Chem. 276:38121-38138.
25. Hagood, J.S., et al. 2005. Loss of fibroblast Thy-1 expression correlates with lung fibrogenesis. Am. J. Pathol. 167:365-379.
26. Kubo, M., et al. 2003. Persistent down-regulation of Fli1, a suppressor of collagen transcription, in fibrotic scleroderma skin. Am. J. Pathol. 163:571-581.
27. Denton, C.P., et al. 2005. Activation of key profibrotic mechanisms in transgenic fibroblasts expressing kinase-deficient type II Transforming growth factor-{beta} receptor. J. Biol. Chem. 280:16053-16065.
28. Kahaleh, M.B., Sherer, G.K., and LeRoy, E.C. 1979. Endothelial injury in scleroderma. J. Exp. Med. 149:1326-1335.
29. Kahaleh, M.B. 2004. Raynaud phenomenon and the vascular disease in scleroderma. Curr. Opin. Rheumatol. 16:718-722.
30. Cerinic, M.M., et al. 2003. Blood coagulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis. Semin. Arthritis Rheum. 32:285-295.
31. Vancheeswaran, R., Azam, A., Black, C., and Dashwood, M.R. 1994. Localization of endothelin-1 and its binding sites in scleroderma skin. J. Rheumatol. 21:1268-1276.
32. Cambrey, A.D., et al. 1994. Increased levels of endothelin-1 in bronchoalveolar lavage fluid from patients with systemic sclerosis contribute to fibroblast mitogenic activity in vitro. Am. J. Respir. Cell Mol. Biol. 11:439-445.
33. Flavahan, N.A., Flavahan, S., Mitra, S., and Chotani, M.A. 2003. The vasculopathy of Raynaud's phenomenon and scleroderma. Rheum. Dis. Clin. North Am. 29:275-291.
34. Distler, O., et al. 2004. Uncontrolled expression of vascular endothelial growth factor and its receptors leads to insufficient skin angiogenesis in patients with systemic sclerosis. Circ. Res. 95:109-116.
35. Davies, C.A., Jeziorska, M., Freemont, A.J., and Herrick, A.L. 2006. The differential expression of VEGF, VEGFR-2, and GLUT-1 proteins in disease subtypes of systemic sclerosis. Hum. Pathol. 37:190-197.
36. Kuwana, M., Okazaki, Y., Yasuoka, H., Kawakami, Y., and Ikeda, Y. 2004. Defective vasculogenesis in systemic sclerosis. Lancet. 364:603-610.
37. Del Papa, N.D., et al. 2006. Bone marrow endothelial progenitors are defective in systemic sclerosis. Arthritis Rheum. 54:2605-2615.
38. Artlett, C.M. 2005. Immunology of systemic sclerosis. Front. Biosci. 10:1707-1719.
39. Sakkas, L.I., et al. 2002. Oligoclonal T cell expansion in the skin of patients with systemic sclerosis. J. Immunol. 168:3649-3659.
40. Wynn, T.A. 2004. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat. Rev. Immunol. 4:583-594.
41. Wangoo, A., et al. 2001. Contribution of Th1 and Th2 cells to protection and pathology in experimental models of granulomatous lung disease. J. Immunol. 166:3432-3439.
42. Lakos, G., Melichian, D., Wu, M., and Varga, J. 2007. Increased bleomycin-induced skin fibrosis in mice lacking the Th1-specific transcription factor T-bet. Pathobiology. In press.
43. Tan, F.K., et al. 2006. Signatures of differentially regulated interferon gene expression and vasculotrophism in the peripheral blood cells of systemic sclerosis patients. Rheumatology (Oxford). 45:694-702.
44. Mavalia, C., et al. 1997. Type 2 helper T-cell predominance and high CD30 expression in systemic sclerosis. Am. J. Pathol. 151:1751-1758.
45. Atamas, S.P., et al. 1999. Production of type 2 cytokines by CD8+ lung cells is associated with greater decline in pulmonary function in patients with systemic sclerosis. Arthritis Rheum. 42:1168-1178.
46. Rottoli, P., et al. 2005. Cytokine profile and proteome analysis in bronchoalveolar lavage of patients with sarcoidosis, pulmonary fibrosis associated with systemic sclerosis and idiopathic pulmonary fibrosis. Proteomics. 5:1423-1430.
47. Hu, P.Q., Fertig, N., Medsger, T.A., Jr., and Wright, T.M. 2003. Correlation of serum anti-DNA topoisomerase I antibody levels with disease severity and activity in systemic sclerosis. Arthritis Rheum. 48:1363-1373.
48. Harris, M.L., and Rosen, A. 2003. Autoimmunity in scleroderma: the origin, pathogenetic role, and clinical significance of autoantibodies. Curr. Opin. Rheumatol. 15:778-784.
49. Carvalho, D., Savage, C.O., Black, C.M., and Pearson, J.D. 1996. IgG antiendothelial cell autoantibodies from scleroderma patients induce leukocyte adhesion to human vascular endothelial cells in vitro. Induction of adhesion molecule expression and involvement of endothelium-derived cytokines. J. Clin. Invest. 97:111-119.
50. Henault, J., Robitaille, G., Senecal, J.L., and Raymond, Y. 2006. DNA topoisomerase I binding to fibroblasts induces monocyte adhesion and activation in the presence of anti-topoisomerase I autoantibodies from systemic sclerosis patients. Arthritis Rheum. 54:963-973.
51. Baroni, S.S., et al. 2006. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N. Engl. J. Med. 354:2667-2676.
52. Whitfield, M.L., et al. 2003. Systemic and cell type-specific gene expression patterns in scleroderma skin. Proc. Natl. Acad. Sci. U. S. A. 100:12319-12324.
53. Sato, S., Fujimoto, M., Hasegawa, M., and Takehara, K. 2004. Altered blood B lymphocyte homeostasis in systemic sclerosis: expanded naive B cells and diminished but activated memory B cells. Arthritis Rheum. 50:1918-1927.
54. Sato, S., et al. 2000. Quantitative genetic variation in CD19 expression correlates with autoimmunity. J. Immunol. 165:6635-6643.
55. Hasegawa, M., et al. 2006. B-lymphocyte depletion reduces skin fibrosis and autoimmunity in the tight-skin mouse model for systemic sclerosis. Am. J. Pathol. 169:954-966.
56. Matsushita, T., et al. 2006. Elevated serum BAFF levels in patients with systemic sclerosis: enhanced BAFF signaling in systemic sclerosis B lymphocytes. Arthritis Rheum. 54:192-201.
57. Denton, C.P., Black, C.M., and Abraham, D.J. 2006. Mechanisms and consequences of fibrosis in systemic sclerosis. Nat. Clin. Pract. Rheumatol. 2:134-144.
58. Varga, J., and Bashey, R.I. 1995. Regulation of connective tissue synthesis in systemic sclerosis. Int. Rev. Immunol. 12:187-199.
59. Ramirez, F., Tanaka, S., and Bou-Gharios, G. 2006. Transcriptional regulation of the human alpha 2(I) collagen gene (COL1A2), an informative model system to study fibrotic diseases. Matrix Biol. 25:365-372.
60. Pannu, J., and Trojanowska, M. 2004. Recent advances in fibroblast signaling and biology in scleroderma. Curr. Opin. Rheumatol. 16:739-745.
61. Abraham, D.J., Exckes, B., Rajkumar, V., and Krieg, T. 2007. New developments in fibroblast and myofibroblast biology: implications for fibrosis and scleroderma. Curr. Rheumatol. Rep. In press.
62. Chang, H.Y., et al. 2002. Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc. Natl. Acad. Sci. U. S. A. 99:12877-12882.
63. Desmouliere, A., Chaponnier, C., and Gabbiani, G. 2005. Tissue repair, contraction, and the myofibroblast. Wound Repair Regen. 13:7-12.
64. Jelaska, A., Arakawa, M., Broketa, G., and Korn, J.H. 1996. Heterogeneity of collagen synthesis in normal and systemic sclerosis skin fibroblasts. Increased proportion of high collagen-producing cells in systemic sclerosis fibroblasts. Arthritis Rheum. 39:1338-1346.
65. Rajkumar, V.S., et al. 2005. Shared expression of phenotypic markers in systemic sclerosis indicates a convergence of pericytes and fibroblasts to a myofibroblast lineage in fibrosis. Arthritis Res. Ther. 7:1113-1123.
66. Yamagishi, S., and Imaizumi, T. 2005. Pericyte biology and diseases. Int. J. Tissue React. 27:125-135.
67. Kalluri, R., and Neilson, E.G. 2003. Epithelial-mesenchymal transition and its implications for fibrosis. J. Clin. Invest. 112:1776-1784. doi:10.1172/JCI200320530.
68. Abe, R., Donnelly, S.C., Peng, T., Bucala, R., and Metz, C.N. 2001. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J. Immunol. 166:7556-7562.
69. Cipriani, P., et al. 2006. Differential expression of stromal cell-derived factor 1 and its receptor CXCR4 in the skin and endothelial cells of systemic sclerosis patients: Pathogenetic implications. Arthritis Rheum. 54:3022-3033.
70. Phillips, R.J. 2004. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J. Clin. Invest. 114:438-446. doi:10.1172/JCI200420997.
71. Kuwana, M., et al. 2003. Human circulating CD14+ monocytes as a source of progenitors that exhibit mesenchymal cell differentiation. J. Leukoc. Biol. 74:833-845.
72. Blobe, G.C., Schiemann, W.P., and Lodish, H.F. 2000. Role of transforming growth factor beta in human disease. N. Engl. J. Med. 342:1350-1358.
73. Annes, J.P., Munger, J.S., and Rifkin, D.B. 2003. Making sense of latent TGFbeta activation. J. Cell Sci. 116:217-224.
74. Massague, J., and Gomis, R.R. 2006. The logic of TGFbeta signaling. FEBS Lett. 580:2811-2820.
75. Moustakas, A., and Heldin, C.H. 2005. Non-Smad TGF-beta signals. J. Cell Sci. 118:3573-3584.
76. Daniels, C.E., et al. 2004. Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis. J. Clin. Invest. 114:1308-1316. doi:10.1172/JCI200419603.
77. Chen, S.J., et al. 2006. The early-immediate gene EGR-1 is induced by transforming growth factor-beta and mediates stimulation of collagen gene expression. J. Biol. Chem. 281:21183-21197.
78. Leask, A., and Abraham, D.J. 2006. All in the CCN family: essential matricellular signaling modulators emerge from the bunker. J. Cell Sci. 119:4803-4810.
79. Igarashi, A., et al. 1996. Connective tissue growth factor gene expression in tissue sections from localized scleroderma, keloid, and other fibrotic skin disorders. J. Invest. Dermatol. 106:729-733.
80. Gay, S., Jones, R.E., Jr., Huang, G.Q., and Gay, R.E. 1989. Immunohistologic demonstration of platelet-derived growth factor (PDGF) and sis-oncogene expression in scleroderma. J. Invest. Dermatol. 92:301-303.
81. Ludwicka, A., et al. 1995. Elevated levels of platelet derived growth factor and transforming growth factor-beta 1 in bronchoalveolar lavage fluid from patients with scleroderma. J. Rheumatol. 22:1876-1883.
82. Postlethwaite, A.E., Holness, M.A., Katai, H., and Raghow, R. 1992. Human fibroblasts synthesize elevated levels of extracellular matrix proteins in response to interleukin 4. J. Clin. Invest. 90:1479-1485.
83. Hasegawa, M., Fujimoto, M., Kikuchi, K., and Takehara, K. 1997. Elevated serum levels of interleukin 4 (IL-4), IL-10, and IL-13 in patients with systemic sclerosis. J. Rheumatol. 24:328-332.
84. Sakkas, L.I., et al. 1999. Increased levels of alternatively spliced interleukin 4 (IL-4delta2) transcripts in peripheral blood mononuclear cellsfrom patients with systemic sclerosis. Clin. Diagn. Lab. Immunol. 6:660-664.
85. Tsuji-Yamada, J., Nakazawa, M., Minami, M., and Sasaki, T. 2001. Increased frequency of interleukin 4 producing CD4+ and CD8+ cells in peripheral blood from patients with systemic sclerosis. J. Rheumatol. 28:1252-1258.
86. Salmon-Ehr, V. 1996. Expression of interleukin-4 in scleroderma skin specimens and scleroderma fibroblast cultures. Potential role in fibrosis. Arch. Dermatol. 132:802-806.
87. Jinnin, M., Ihn, H., Yamane, K., and Tamaki, K. 2004. Interleukin-13 stimulates the transcription of the human alpha2(I) collagen gene in human dermal fibroblasts. J. Biol. Chem. 279:41783-41791.
88. Kaviratne, M., et al. 2004. IL-13 activates a mechanism of tissue fibrosis that is completely TGF-beta independent. J. Immunol. 173:4020-4029.
89. Distler, J.H., et al. 2006. Monocyte chemoattractant protein 1 released from glycosaminoglycans mediates its profibrotic effects in systemic sclerosis via the release of interleukin-4 from T cells. Arthritis Rheum. 54:214-225.
90. Galindo, M., et al. 2001. Chemokine expression by systemic sclerosis fibroblasts: abnormal regulation of monocyte chemoattractant protein 1 expression. Arthritis Rheum. 44:1382-1386.
91. Kodera, M., et al. 2005. Serum pulmonary and activation-regulated chemokine/CCL18 levels in patients with systemic sclerosis: a sensitive indicator of active pulmonary fibrosis. Arthritis Rheum. 52:2889-2896.
92. Carulli, M.T., et al. 2005. Chemokine receptor CCR2 expression by systemic sclerosis fibroblasts: evidence for autocrine regulation of myofibroblast differentiation. Arthritis Rheum. 52:3772-3782.
93. Ong, V.H., et al. 2003. Monocyte chemoattractant protein 3 as a mediator of fibrosis: Overexpression in systemic sclerosis and the type 1 tight-skin mouse. Arthritis Rheum. 48:1979-1991.
94. Jimenez, S.A., Freundlich, B., and Rosenbloom, J. 1984. Selective inhibition of human diploid fibroblast collagen synthesis by interferons. J. Clin. Invest. 74:1112-1116.
95. Ghosh, A.K., et al. 2001. 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. 276:11041-11048.
96. Varga, J. 1997. Recombinant cytokine treatment for scleroderma. Can the antifibrotic potential of interferon-gamma be realized clinically? Arch. Dermatol. 133:637-642.
97. Arai, T., et al. 2000. Introduction of the interleukin-10 gene into mice inhibited bleomycin-induced lung injury in vivo. Am. J. Physiol. Lung Cell. Mol. Physiol. 278:L914-L922.
98. Chen, S.J., et al. 1999. Stimulation of type I collagen transcription in human skin fibroblasts by TGF-beta: involvement of Smad 3. J. Invest. Dermatol. 112:49-57.
99. Dong, C., et al. 2002. Deficient Smad7 expression: a putative molecular defect in scleroderma. Proc. Natl. Acad. Sci. U. S. A. 99:3908-3913.
100. Chen, S.J., Artlett, C.M., Jimenez, S.A., and Varga, J. 1998. Modulation of human alpha1(I) procollagen gene activity by interaction with Sp1 and Sp3 transcription factors in vitro. Gene. 215:101-110.
101. Czuwara-Ladykowska, J., Shirasaki, F., Jackers, P., Watson, D.K., and Trojanowska, M. 2001. Fli-1 inhibits collagen type I production in dermal fibroblasts via an Sp1-dependent pathway. J. Biol. Chem. 276:20839-20848.
102. Ghosh, A.K., Bhattacharyya, S., and Varga, J. 2004. The tumor suppressor p53 abrogates Smad-dependent collagen gene induction in mesenchymal cells. J. Biol. Chem. 279:47455-47463.
103. Ghosh, A.K., et al. 2004. Disruption of transforming growth factor beta signaling and profibrotic responses in normal skin fibroblasts by peroxisome proliferator-activated receptor gamma. Arthritis Rheum. 50:1305-1318.
104. LeRoy, E.C. 1974. Increased collagen synthesis by scleroderma skin fibroblasts in vitro: a possible defect in the regulation or activation of the scleroderma fibroblast. J. Clin. Invest. 54:880-889.
105. Trojanowska, M. 2004. What did we learn by studying scleroderma fibroblasts? Clin. Exp. Rheumatol. 22(Suppl. 3):S59-S63.
106. Gardner, H., et al. 2006. Gene profiling of scleroderma skin reveals robust signatures of disease that are imperfectly reflected in the transcript profiles of explanted fibroblasts. Arthritis Rheum. 54:1961-1973.
107. Tan, F.K., et al. 2005. Classification analysis of the transcriptosome of nonlesional cultured dermal fibroblasts from systemic sclerosis patients with early disease. Arthritis Rheum. 52:865-876.
108. Mimura, Y., et al. 2005. Constitutive phosphorylation of focal adhesion kinase is involved in the myofibroblast differentiation of SSc fibroblasts. J. Invest. Dermatol. 124:886-892.
109. Santiago, B., Galindo, M., Rivero, M., and Pablos, J.L. 2001. Decreased susceptibility to Fas-induced apoptosis of systemic sclerosis dermal fibroblasts. Arthritis Rheum. 44:1667-1676.
110. Jun, J.B., et al. 2005. SSc fibroblasts demonstrate enhanced activation of Akt (protein kinase B) in situ. J. Invest. Dermatol. 124:298-303.
111. Jelaska, A., and Korn, J.H. 2000. Role of apoptosis and transforming growth factor beta1 in fibroblast selection and activation in systemic sclerosis. Arthritis Rheum. 43:2230-2239.
112. Kawakami, T., et al. 1998. Increased expression of TGF-beta receptors by scleroderma fibroblasts: evidence for contribution of autocrine TGF-beta signaling to scleroderma phenotype. J. Invest. Dermatol. 110:47-51.
113. Pannu, J., Gardner, H., Shearstone, J.R., Smith, E., and Trojanowska, M. 2006. Increased levels of transforming growth factor beta receptor type I and up-regulation of matrix gene program: A model of scleroderma. Arthritis Rheum. 54:3011-3021.
114. Mimura, Y., et al. 2005. Constitutive thrombospondin-1 overexpression contributes to autocrine TGF-beta signaling in cultured scleroderma fibroblasts. Am. J. Pathol. 166:1451-1463.
115. Asano, Y., et al. 2005. Involvement of alphavbeta5 integrin-mediated activation of latent transforming growth factor beta1 in autocrine TGF beta signaling in systemic sclerosis fibroblasts. Arthritis Rheum. 52:2897-2905.
116. Mori, Y., Chen, S.J., and Varga, J. 2003. Expression and regulation of intracellular SMAD signaling in scleroderma skin fibroblasts. Arthritis Rheum. 48:1964-1978.
117. Bhattacharyya, S., et al. 2005. Fibroblast expression of the coactivator p300 governs the intensity of profibrotic response to transforming growth factor beta. Arthritis Rheum. 52:1248-1258.
118. Ihn, H., Yamane, K., Asano, Y., Jinnin, M., and Tamaki, K. 2006. Constitutively phosphorylated Smad3 interacts with Sp1 and p300 in scleroderma fibroblasts. Rheumatology (Oxford). 45:157-165.
119. Wang, Y., Fan, P.S., and Kahaleh, B. 2006. Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts. Arthritis Rheum. 54:2271-2279.
120. Shi-Wen, X., et al. 2006. Constitutive ALK5-independent c-Jun N-terminal kinase activation contributes to endothelin-1 overexpression in pulmonary fibrosis: evidence of an autocrine endothelin loop operating through the endothelin A and B receptors. Mol. Cell. Biol. 26:5518-5527.
121. Ishida, W., et al. 2006. Intracellular TGF-beta receptor blockade abrogates Smad-dependent fibroblast activation in vitro and in vivo. J. Invest. Dermatol. 126:1733-1744.
122. Chen, Y., et al. 2006. Contribution of activin receptor-like kinase 5 (transforming growth factor beta receptor type I) signaling to the fibrotic phenotype of scleroderma fibroblasts. Arthritis Rheum. 54:1309-1316.
123. Eckes, B., et al. 2006. Mechanical Tension and Integrin alpha2beta1 Regulate Fibroblast Functions. J. Invest. Dermatol. 126(Suppl.): 66-72.