Following the Molecular Pathways toward an Understanding of the Pathogenesis of Systemic Sclerosis
Authors: Sergio A. Jimenez
Journal: Annals of Internal Medicine (2004)

Reviews6 January 2004Following the Molecular Pathways toward an Understanding of the Pathogenesis of Systemic SclerosisSergio A. Jimenez, MD and Chris T. Derk, MDSergio A. Jimenez, MDFrom Thomas Jefferson University, Philadelphia, Pennsylvania. and Chris T. Derk, MDFrom Thomas Jefferson University, Philadelphia, Pennsylvania.Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-140-1-200401060-00010 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Clinical PrinciplesSystemic sclerosis is an autoimmune connective tissue disorder of unknown cause.It is clinically heterogeneous, ranging from limited skin involvement to diffuse skin sclerosis with severe internal organ involvement.The Raynaud phenomenon, swelling of the extremities, and diffuse arthralgias often precede the onset of skin tightness and induration.Visceral involvement with fibrosis, microvascular alterations, and mononuclear cell infiltration of the gastrointestinal tract, lungs, heart, and kidneys is present to a variable extent in most patients.Autoantibodies, some with very high specificity, are present almost universally.Mortality and morbidity are substantial and are directly related to the extent of the fibrotic and microvascular alterations.A better ...References1. LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA, et al . Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988;15:202-5. [PMID: 3361530] MedlineGoogle Scholar2. Lally EV, Jimenez SA, Kaplan SR. Progressive systemic sclerosis: mode of presentation, rapidly progressive disease course, and mortality based on an analysis of 91 patients. Semin Arthritis Rheum. 1988;18:1-13. [PMID: 3187542] CrossrefMedlineGoogle Scholar3. Rodnan GP. Progressive systemic sclerosis: clinical features and pathogenesis of cutaneous involvement (scleroderma). Clin Rheum Dis. 1979;5:49-79. CrossrefGoogle Scholar4. Fritzler MJ, Kinsella TD. The CREST syndrome: a distinct serologic entity with anticentromere antibodies. Am J Med. 1980;69:520-6. [PMID: 6968511] CrossrefMedlineGoogle Scholar5. Block JA, Sequeira W. Raynaud's phenomenon. Lancet. 2001;357:2042-8. [PMID: 11438158] CrossrefMedlineGoogle Scholar6. Pope JE. Musculoskeletal involvement in scleroderma. Rheum Dis Clin North Am. 2003;29:391-408. [PMID: 12841301] CrossrefMedlineGoogle Scholar7. Rose S, Young MA, Reynolds JC. Gastrointestinal manifestations of scleroderma. Gastroenterol Clin North Am. 1998;27:563-94. [PMID: 9891698] CrossrefMedlineGoogle Scholar8. Co HT, Block JA, Sequeira W. Scleroderma lung: pathogenesis, evaluation, and current therapy. Am J Ther. 2000;7:321-4. [PMID: 11317180] CrossrefMedlineGoogle Scholar9. Coghlan JG, Mukerjee D. The heart and pulmonary vasculature in scleroderma: clinical features and pathobiology. Curr Opin Rheumatol. 2001;13:495-9. [PMID: 11698727] CrossrefMedlineGoogle Scholar10. Deswal A, Follansbee WP. Cardiac involvement in scleroderma. Rheum Dis Clin North Am. 1996;22:841-60. [PMID: 8923599] CrossrefMedlineGoogle Scholar11. Steen VD. Scleroderma renal crisis. Rheum Dis Clin North Am. 2003;29:315-33. [PMID: 12841297] CrossrefMedlineGoogle Scholar12. Gordon MB, Klein I, Dekker A, Rodnan GP, Medsger TA. Thyroid disease in progressive systemic sclerosis: increased frequency of glandular fibrosis and hypothyroidism. Ann Intern Med. 1981;95:431-5. [PMID: 7283293] LinkGoogle Scholar13. Lally EV, Jimenez SA. Impotence in progressively systemic sclerosis. Ann Intern Med. 1981;95:150-3. [PMID: 6789736] LinkGoogle Scholar14. Cipoletti JF, Buckingham RB, Barnes EL, Peel RL, Mahmood K, Cignetti FE, et al . Sjogren's syndrome in progressive systemic sclerosis. Ann Intern Med. 1977;87:535-41. [PMID: 921080] LinkGoogle Scholar15. Fleischmajer R, Perlish JS, Reeves JR. Cellular infiltrates in scleroderma skin. Arthritis Rheum. 1977;20:975-84. [PMID: 861067] CrossrefMedlineGoogle Scholar16. Jimenez SA. Cellular immune dysfunction and the pathogenesis of scleroderma. Semin Arthritis Rheum. 1983;13:104-13. [PMID: 6353581] CrossrefMedlineGoogle Scholar17. Feghali-Bostwick C, Medsger TA, Wright TM. Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Arthritis Rheum. 2003;48:1956-63. [PMID: 12847690] CrossrefMedlineGoogle Scholar18. Jimenez SA, Diaz A, Khalili K. Retroviruses and the pathogenesis of systemic sclerosis. Int Rev Immunol. 1995;12:159-75. [PMID: 7650419] CrossrefMedlineGoogle Scholar19. Dang H, Dauphinee MJ, Talal N, Garry RF, Seibold JR, Medsger TA, et al . Serum antibody to retroviral gag proteins in systemic sclerosis. Arthritis Rheum. 1991;34:1336-7. [PMID: 1930323] CrossrefMedlineGoogle Scholar20. Pandey JP, LeRoy EC. Human cytomegalovirus and the vasculopathies of autoimmune diseases (especially scleroderma), allograft rejection, and coronary restenosis. Arthritis Rheum. 1998;41:10-5. [PMID: 9433864] CrossrefMedlineGoogle Scholar21. Neidhart M, Kuchen S, Distler O, Bruhlmann P, Michel BA, Gay RE, et al . Increased serum levels of antibodies against human cytomegalovirus and prevalence of autoantibodies in systemic sclerosis. Arthritis Rheum. 1999;42:389-92. [PMID: 10025936] CrossrefMedlineGoogle Scholar22. Mayes MD. Epidemiologic studies of environmental agents and systemic autoimmune diseases. Environ Health Perspect. 1999;107 Suppl 5 743-8. [PMID: 10502540] MedlineGoogle Scholar23. Diot E, Lesire V, Guilmot JL, Metzger MD, Pilore R, Rogier S, et al . Systemic sclerosis and occupational risk factors: a case–control study. Occup Environ Med. 2002;59:545-9. [PMID: 12151611] CrossrefMedlineGoogle Scholar24. Garabrant DH, Lacey JV, Laing TJ, Gillespie BW, Mayes MD, Cooper BC, et al . Scleroderma and solvent exposure among women. Am J Epidemiol. 2003;157:493-500. [PMID: 12631538] CrossrefMedlineGoogle Scholar25. Johnson RW, Tew MB, Arnett FC. The genetics of systemic sclerosis. Curr Rheumatol Rep. 2002;4:99-107. [PMID: 11890874] CrossrefMedlineGoogle Scholar26. Arnett FC, Howard RF, Tan F, Moulds JM, Bias WB, Durban E, et al . Increased prevalence of systemic sclerosis in a Native American tribe in Oklahoma. Association with an Amerindian HLA haplotype. Arthritis Rheum. 1996;39:1362-70. [PMID: 8702445] CrossrefMedlineGoogle Scholar27. Reveille JD. Ethnicity and race and systemic sclerosis: how it affects susceptibility, severity, antibody genetics, and clinical manifestations. Curr Rheumatol Rep. 2003;5:160-7. [PMID: 12628048] CrossrefMedlineGoogle Scholar28. Hata R, Akai J, Kimura A, Ishikawa O, Kuwana M, Shinkai H. Association of functional microsatellites in the human type I collagen alpha2 chain (COL1A2) gene with systemic sclerosis. Biochem Biophys Res Commun. 2000;272:36-40. [PMID: 10872800] CrossrefMedlineGoogle Scholar29. Crilly A, Hamilton J, Clark CJ, Jardine A, Madhok R. Analysis of transforming growth factor beta1 gene polymorphisms in patients with systemic sclerosis. Ann Rheum Dis. 2002;61:678-81. [PMID: 12117671] CrossrefMedlineGoogle Scholar30. Awad MR, El-Gamel A, Hasleton P, Turner DM, Sinnott PJ, Hutchinson IV. Genotypic variation in the transforming growth factor-beta1 gene: association with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. Transplantation. 1998;66:1014-20. [PMID: 9808485] CrossrefMedlineGoogle Scholar31. Tan FK, Wang N, Kuwana M, Chakraborty R, Bona CA, Milewicz DM, et al . Association of fibrillin 1 single-nucleotide polymorphism haplotypes with systemic sclerosis in Choctaw and Japanese populations. Arthritis Rheum. 2001;44:893-901. [PMID: 11315929] CrossrefMedlineGoogle Scholar32. Artlett CM, Smith JB, Jimenez SA. Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis. N Engl J Med. 1998;338:1186-91. [PMID: 9554859] CrossrefMedlineGoogle Scholar33. Artlett CM. Microchimerism and scleroderma: an update. Curr Rheumatol Rep. 2003;5:154-9. [PMID: 12628047] CrossrefMedlineGoogle Scholar34. Nelson JL. Microchimerism and HLA relationships of pregnancy: implications for autoimmune diseases. Curr Rheumatol Rep. 2001;3:222-9. [PMID: 11352791] CrossrefMedlineGoogle Scholar35. Maloney S, Smith A, Furst DE, Myerson D, Rupert K, Evans PC, et al . Microchimerism of maternal origin persists into adult life. J Clin Invest. 1999;104:41-7. [PMID: 10393697] CrossrefMedlineGoogle Scholar36. Ohtsuka T, Miyamoto Y, Yamakage A, Yamazaki S. Quantitative analysis of microchimerism in systemic sclerosis skin tissue. Arch Dermatol Res. 2001;293:387-91. [PMID: 11686513] CrossrefMedlineGoogle Scholar37. Burastero SE, Galbiati S, Vassallo A, Sabbadini MG, Bellone M, Marchionni L, et al . Cellular microchimerism as a lifelong physiologic status in parous women: an immunologic basis for its amplification in patients with systemic sclerosis. Arthritis Rheum. 2003;48:1109-16. [PMID: 12687555] CrossrefMedlineGoogle Scholar38. Ho KT, Reveille JD. The clinical relevance of autoantibodies in scleroderma. Arthritis Res Ther. 2003;5:80-93. [PMID: 12718748] MedlineGoogle Scholar39. Roumm AD, Whiteside TL, Medsger TA, Rodnan GP. Lymphocytes in the skin of patients with progressive systemic sclerosis. Quantification, subtyping, and clinical correlations. Arthritis Rheum. 1984;27:645-53. [PMID: 6375682] CrossrefMedlineGoogle Scholar40. Kraling BM, Maul GG, Jimenez SA. Mononuclear cellular infiltrates in clinically involved skin from patients with systemic sclerosis of recent onset predominantly consist of monocytes/macrophages. Pathobiology. 1995;63:48-56. [PMID: 7546275] CrossrefMedlineGoogle Scholar41. Chizzolini C. T lymphocyte and fibroblast interactions: the case of skin involvement in systemic sclerosis and other examples. Springer Semin Immunopathol. 1999;21:431-50. [PMID: 10945035] CrossrefMedlineGoogle Scholar42. Sakkas LI, Xu B, Artlett CM, Lu S, Jimenez SA, Platsoucas CD. Oligoclonal T cell expansion in the skin of patients with systemic sclerosis. J Immunol. 2002;168:3649-59. [PMID: 11907131] CrossrefMedlineGoogle Scholar43. Ferrarini M, Steen V, Medsger TA, Whiteside TL. Functional and phenotypic analysis of T lymphocytes cloned from the skin of patients with systemic sclerosis. Clin Exp Immunol. 1990;79:346-52. [PMID: 1969335] CrossrefMedlineGoogle Scholar44. Shimizu Y, Van Seventer GA, Horgan KJ, Shaw S. Regulated expression and binding of three VLA (β 1) integrin receptors on T cells. Nature. 1990;345:250-3. [PMID: 2139716] CrossrefMedlineGoogle Scholar45. White B. Immunopathogenesis of systemic sclerosis. Rheum Dis Clin North Am. 1996;22:695-708. [PMID: 8923591] CrossrefMedlineGoogle Scholar46. Postlethwaite AE. Role of T cells and cytokines in effecting fibrosis. Int Rev Immunol. 1995;12:247-58. [PMID: 7650423] CrossrefMedlineGoogle Scholar47. Roberts AB. Molecular and cell biology of TGF-β. Miner Electrolyte Metab. 1998;24:111-9. [PMID: 9525693] CrossrefMedlineGoogle Scholar48. Varga J, Rosenbloom J, Jimenez SA. Transforming growth factor β (TGF β) causes a persistent increase in steady-state amounts of type I and type III collagen and fibronectin mRNAs in normal human dermal fibroblasts. Biochem J. 1987;247:597-604. [PMID: 3501287] CrossrefMedlineGoogle Scholar49. 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. [PMID: 11229480] CrossrefMedlineGoogle Scholar50. Massague J. How cells read TGF-β signals. Nat Rev Mol Cell Biol. 2000;1:169-78. [PMID: 11252892] CrossrefMedlineGoogle Scholar51. Attisano L, Wrana JL. Signal transduction by the TGF-β superfamily. Science. 2002;296:1646-7. [PMID: 12040180] CrossrefMedlineGoogle Scholar52. Varga J. Scleroderma and Smads: dysfunctional Smad family dynamics culminating in fibrosis. Arthritis Rheum. 2002;46:1703-13. [PMID: 12124852] CrossrefMedlineGoogle Scholar53. 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. [PMID: 11904440] CrossrefMedlineGoogle Scholar54. Leask A, Holmes A, Abraham DJ. Connective tissue growth factor: a new and important player in the pathogenesis of fibrosis. Curr Rheumatol Rep. 2002;4:136-42. [PMID: 11890879] CrossrefMedlineGoogle Scholar55. Jimenez SA, Saitta B. Alterations in the regulation of expression of the α 1(I) collagen gene (COL1A1) in systemic sclerosis (scleroderma). Springer Semin Immunopathol. 1999;21:397-414. [PMID: 10945033] MedlineGoogle Scholar56. Trojanowska M. Molecular aspects of scleroderma. Front Biosci. 2002;7:d608-18. [PMID: 11861221] CrossrefMedlineGoogle Scholar57. Ghosh AK. Factors involved in the regulation of type I collagen gene expression: implication in fibrosis. Exp Biol Med (Maywood). 2002;227:301-14. [PMID: 11976400] CrossrefMedlineGoogle Scholar58. Hitraya EG, Varga J, Artlett CM, Jimenez SA. Identification of elements in the promoter region of the alpha1(I) procollagen gene involved in its up-regulated expression in systemic sclerosis. Arthritis Rheum. 1998;41:2048-58. [PMID: 9811061] CrossrefMedlineGoogle Scholar59. 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. [PMID: 11037883] CrossrefMedlineGoogle Scholar60. Rippe RA, Almounajed G, Brenner DA. Sp1 binding activity increases in activated Ito cells. Hepatology. 1995;22:241-51. [PMID: 7601417] MedlineGoogle Scholar61. Nehls MC, Brenner DA, Gruss HJ, Dierbach H, Mertelsmann R, Herrmann F. Mithramycin selectively inhibits collagen-α 1(I) gene expression in human fibroblast. J Clin Invest. 1993;92:2916-21. [PMID: 7504695] CrossrefMedlineGoogle Scholar62. Gaidarova S, Jimenez SA. Inhibition of basal and transforming growth factor-β-induced stimulation of COL1A1 transcription by the DNA intercalators, mitoxantrone and WP631, in cultured human dermal fibroblasts. J Biol Chem. 2002;277:38737-45. [PMID: 12138160] CrossrefMedlineGoogle Scholar63. Saitta B, Gaidarova S, Cicchillitti L, Jimenez SA. CCAAT binding transcription factor binds and regulates human COL1A1 promoter activity in human dermal fibroblasts: demonstration of increased binding in systemic sclerosis fibroblasts. Arthritis Rheum. 2000;43:2219-29. [PMID: 11037881] CrossrefMedlineGoogle Scholar64. Widom RL, Culic I, Lee JY, Korn JH. Cloning and characterization of hcKrox, a transcriptional regulator of extracellular matrix gene expression. Gene. 1997;198:407-20. [PMID: 9370309] CrossrefMedlineGoogle Scholar65. Campbell PM, LeRoy EC. Pathogenesis of systemic sclerosis: a vascular hypothesis. Semin Arthritis Rheum. 1975;4:351-68. [PMID: 1135634] CrossrefMedlineGoogle Scholar66. Drenk F, Deicher HR. Pathophysiological effects of endothelial cytotoxic activity derived from sera of patients with progressive systemic sclerosis. J Rheumatol. 1988;15:468-74. [PMID: 3379623] MedlineGoogle Scholar67. Kahaleh MB, LeRoy EC. Endothelial injury in scleroderma. A protease mechanism. J Lab Clin Med. 1983;101:553-60. [PMID: 6339651] MedlineGoogle Scholar68. Renaudineau Y, Revelen R, Levy Y, Salojin K, Gilburg B, Shoenfeld Y, et al . Anti-endothelial cell antibodies in systemic sclerosis. Clin Diagn Lab Immunol. 1999;6:156-60. [PMID: 10066646] CrossrefMedlineGoogle Scholar69. Herrick AL. Vascular function in systemic sclerosis. Curr Opin Rheumatol. 2000;12:527-33. [PMID: 11092203] CrossrefMedlineGoogle Scholar70. Xu S, Denton CP, Holmes A, Dashwood MR, Abraham DJ, Black CM. Endothelins: effect on matrix biosynthesis and proliferation in normal and scleroderma fibroblasts. J Cardiovasc Pharmacol. 1998;31 Suppl 1:S360-3. [PMID: 9595482] CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAffiliations: From Thomas Jefferson University, Philadelphia, Pennsylvania.For definition of terms used, see Glossary.Acknowledgments: The authors thank Kate Salmon for expert assistance in the preparation of the manuscript and M. Sonsoles Piera-Velazquez, PhD, for assistance in the preparation of some of the illustrations.Grant Support: By National Institutes of Health Grant AR19616. Dr. Derk was supported by National Institutes of Health Training Grant AR07583.Disclosures: None disclosed.Corresponding Author: Sergio A. Jimenez, MD, Division of Rheumatology, Thomas Jefferson University, 233 South 10th Street, Room 509 BLSB, Philadelphia, PA 19107-5541.Current Author Addresses: Dr. Jimenez: Division of Rheumatology, Thomas Jefferson University, 233 South 10th Street, Room 509 BLSB, Philadelphia, PA 19107-5541.Dr. Derk: Division of Rheumatology, Thomas Jefferson University, 1025 Walnut Street, Room 613 Curtis, Philadelphia, PA 19107-5541. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byOral Mesenchymal Stromal Cells in Systemic Sclerosis: Characterization and Response to a Hyaluronic-Acid-Based BiomaterialIncidence and prevalence of systemic sclerosis globally: a comprehensive systematic review and meta-analysisAltered CD4+ T cell and cytokine levels in peripheral blood and skin samples from systemic sclerosis patients and IL-35 in CD4+ T cell growthCalprotectin, an available prognostic biomarker in systemic sclerosis: a systematic reviewSystemic Sclerosis-Associated Pulmonary Hypertension: Spectrum and ImpactSafety and Efficacy of B-Cell Depletion with Rituximab for the Treatment of Systemic Sclerosis Associated Pulmonary Arterial Hypertension: A Multi-center, Double-blind, Randomized, Placebo-controlled TrialClassical Disease-Specific Autoantibodies in Systemic Sclerosis: Clinical Features, Gene Susceptibility, and Disease StratificationComparison of Effect on Sicca Symptoms of Anticentromere Antibody–positive Sjögren Syndrome and Primary Sjögren Syndrome AloneSystemic sclerosis patients are at higher risk of hyperthyroidism and have a worse survival than those without hyperthyroidism: A nationwide population‐based cohort studyOff‐label use of aprepitant for scleroderma‐associated nausea and vomiting: A case reportAssociation Between Exposure to Heavy Metals and Systemic Sclerosis: the Levels of Al, Cd, Hg, and Pb in Blood and Urine of PatientsPathogenesisThe effects of upper and lower limb exercise on the microvascular reactivity in limited cutaneous systemic sclerosis patientsA prospective, open-label, non-comparative study of ambrisentan with anti-fibrotic agent combination therapy in the treatment of diffuse systemic sclerosisDeterminants of mortality in systemic sclerosis: a focused reviewExisting and novel biomarkers for precision medicine in systemic sclerosisExpressions of p53 and PUMA in fibroblasts of systemic sclerosis patients are normal at transcription levelThe challenge of establishing treatment efficacy for cutaneous vascular manifestations of systemic sclerosisN-Formyl Peptide Receptors Induce Radical Oxygen Production in Fibroblasts Derived From Systemic Sclerosis by Interacting With a Cleaved Form of Urokinase ReceptorStudy of the osteoprotegerin/receptor activator of nuclear factor-kB ligand system association with inflammation and atherosclerosis in systemic sclerosisOral rigidity and xerostomia in a 46-year-old manEpigenetics and pathogenesis of systemic sclerosis; the ins and outsExpression of TLR7, TLR9, JAK2, and STAT3 genes in peripheral blood mononuclear cells from patients with systemic sclerosisGastrointestinal and Hepatic Disease in Systemic SclerosisOrofacial consequences of systemic sclerosis: A systematic reviewRXRB Is an MHC-Encoded Susceptibility Gene Associated with Anti-Topoisomerase I Antibody-Positive Systemic SclerosisReview article: pathogenesis and clinical manifestations of gastrointestinal involvement in systemic sclerosisNon-Group 1 Pulmonary Hypertension Associated With Systemic Sclerosis: An Under-studied Patient PopulationPH Professional Network: Screening for Caregiver's Burden in Management of Scleroderma: Pulmonary Arterial HypertensionA protein fragment derived from DNA-topoisomerase I as a novel tumour-associated antigen for the detection of early stage carcinomaOptical Coherence Tomography Imaging of Skin Scarring and FibrosisSystemic SclerodermasHand Function in SclerodermaEarly Growth Response 3 (Egr-3) Is Induced by Transforming Growth Factor-β and Regulates Fibrogenic ResponsesSystemic Sclerosis-Associated Pulmonary Arterial HypertensionPulmonary hypertension in scleroderma and its relation to disease activityRole of Endothelial to Mesenchymal Transition in the Pathogenesis of the Vascular Alterations in Systemic SclerosisErythrocyte glutathione transferase: a non-antibody biomarker for systemic sclerosis, which correlates with severity and activity of the diseaseIdentification of CSK as a systemic sclerosis genetic risk factor through Genome Wide Association Study follow-upMechanism of FibrosisPulmonary HypertensionThe Early Growth Response Gene Egr2 (Alias Krox20) Is a Novel Transcriptional Target of Transforming Growth Factor-β that Is Up-Regulated in Systemic Sclerosis and Mediates Profibrotic ResponsesBilateral Mandibular Condylysis from Systemic Sclerosis: Case Report of Surgical Correction with Bilateral Total Temporomandibular Joint ReplacementPulmonary Arterial Hypertension Related to Scleroderma and Collagen Vascular DiseasesTHE SYSTEMIC SCLERODERMAS AND RELATED DISORDERSGenome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locusNarrative Review: Fibrotic Diseases: Cellular and Molecular Mechanisms and Novel TherapiesJoel Rosenbloom, MD, PhD, Susan V. Castro, PhD, and Sergio A. Jimenez, MDScleroderma Lung DiseaseProteome Analysis of Bronchoalveolar Lavage Fluid in Lung Fibrosis Associated with Systemic SclerosisEssential Roles for Early Growth Response Transcription Factor Egr-1 in Tissue Fibrosis and Wound HealingUnmet Patient Needs in Systemic SclerosisTherapies for scleroderma-related pulmonary arterial hypertensionA non-Smad mechanism of fibroblast activation by transforming growth factor-β via c-Abl and Egr-1: selective modulation by imatinib mesylateAnimal Models of Scleroderma: From Cellular and Molecular Mechanisms to Novel Antifibrotic StrategiesThrombotic MicroangiopathiesCaveolin-1, transforming growth factor-β receptor internalization, and the pathogenesis of systemic sclerosisProteomic Analysis of Exosomes from Human Neural Stem Cells by Flow Field-Flow Fractionation and Nanoflow Liquid Chromatography−Tandem Mass SpectrometryAkt Blockade Downregulates Collagen and Upregulates MMP1 in Human Dermal FibroblastsConnective Tissue DisordersHuman Collagen Krox Up-regulates Type I Collagen Expression in Normal and Scleroderma Fibroblasts through Interaction with Sp1 and Sp3 Transcription FactorsStatins as Immunomodulators in Systemic SclerosisSystemic Sclerosis Mortality in the United StatesConnective Tissue Diseases and the HeartThe X chromosome and systemic sclerosisThe role of allograft inflammatory factor 1 in systemic sclerosisCurrent World LiteratureBosentan for the treatment of systemic sclerosis-associated pulmonary arterial hypertension, pulmonary fibrosis and digital ulcersStimulatory Autoantibodies to the PDGF Receptor in Systemic SclerosisProteasome blockade exerts an antifibrotic activity by coordinately down‐regulating type I collagen and tissue inhibitor of metalloproteinase‐1 and up‐regulating metalloproteinase‐1 production in human dermal fibroblastsThe Lung in Systemic SclerosisScleroderma Fibroblast Survival in AktionTHE SYSTEMIC SCLERODERMAS AND RELATED DISORDERSSystemic SclerosisSklerodermie und Sharp-Syndrom 6 January 2004Volume 140, Issue 1Page: 37-50KeywordsAutoantibodiesCytokinesEndothelial cellsFibroblastsFibrosisGrowth factorsPathogenesisProteinsSclerodermaSystemic diseases ePublished: 6 January 2004 Issue Published: 6 January 2004 Copyright & PermissionsCopyright © 2004 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...