title: Fibrosis--a lethal component of systemic sclerosis.
abstract: Fibrosis is a pathological process characterized by excessive accumulation of connective tissue components in an organ or tissue. Fibrosis is produced by deregulated wound healing in response to chronic tissue injury or chronic inflammation, the hallmarks of rheumatic diseases. Progressive fibrosis, which distorts tissue architecture and results in progressive loss of organ function, is now recognized to be one of the major causes of morbidity and mortality in individuals with one of the most lethal rheumatic disease, systemic sclerosis (SSc). In this Review, we discuss the pathological role of fibrosis in SSc. We discuss the involvement of endothelium and pericyte activation, aberrant immune responses, endoplasmic reticulum stress and chronic tissue injury in the initiation of fibrosis in SSc. We then discuss fibroblast activation and myofibroblast differentiation that occurs in response to these initiating processes and is responsible for excessive accumulation of extracellular matrix. Finally, we discuss the chemical and mechanical signals that drive fibroblast activation and myofibroblast differentiation, which could serve as targets for new therapies for fibrosis in SSc.
authors.affiliation: Shriners Hospital for Children, Division of Surgical Research, McGill University, 1529 Cedar Avenue, Montreal, QC H3G1A6, Canada.
authors.forename: Yuen Yee
authors.initials: YY
authors.lastname: Ho
authors.affiliation: Pulmonary and Critical Care Unit and Centre for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lagares
authors.affiliation: Pulmonary and Critical Care Unit and Centre for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Tager
authors.affiliation: The Toronto Western Research Institute, Division of Orthopaedics, Toronto Western Hospital, The University Health Network, 60 Leonard Avenue, Toronto, ON M5T 2S8, Canada.
authors.forename: Mohit
authors.initials: M
authors.lastname: Kapoor
mesh_terms: D001323:Autoantibodies / Q000276:immunology; D002454:Cell Differentiation; D004721:Endoplasmic Reticulum / Q000502:physiology; D004727:Endothelium / Q000473:pathology; D005347:Fibroblasts / Q000502:physiology; D005355:Fibrosis / Q000276:immunology / Q000503:physiopathology; D006801:Humans; D020286:Pericytes / Q000502:physiology; D012595:Scleroderma, Systemic / Q000276:immunology / Q000473:pathology*; D012867:Skin / Q000473:pathology; D013314:Stress, Mechanical; D014157:Transcription Factors / Q000502:physiology
chemical_list: D001323:Autoantibodies; D014157:Transcription Factors
references.citation: Arthritis Rheum. 2000 Nov;43(11):2464-71
references.pmid: 11083269
references.citation: Autophagy. 2009 Nov;5(8):1217-9
references.pmid: 19829057
references.citation: Growth Factors. 2011 Oct;29(5):196-202
references.pmid: 21740331
references.citation: J Invest Dermatol. 2006 Mar;126(3):561-8
references.pmid: 16397521
references.citation: J Cell Biochem. 2003 Mar 1;88(4):660-72
references.pmid: 12577300
references.citation: Medicine (Baltimore). 2013 Jul;92(4):191-205
references.pmid: 23793108
references.citation: Nat Med. 2010 Sep;16(9):1009-17
references.pmid: 20818376
references.citation: Clin Rheumatol. 2003 May;22(2):102-6
references.pmid: 12740673
references.citation: Arthritis Rheum. 2011 May;63(5):1405-15
references.pmid: 21305523
references.citation: Endocrinology. 2000 Nov;141(11):4021-31
references.pmid: 11089532
references.citation: Cell Mol Life Sci. 2002 Oct;59(10):1640-8
references.pmid: 12475174
references.citation: Curr Rheumatol Rep. 2012 Feb;14(1):56-63
references.pmid: 22083296
references.citation: Biochim Biophys Acta. 2013 Jan;1831(1):42-60
references.pmid: 22867755
references.citation: Lancet. 2004 Aug 14-20;364(9434):603-10
references.pmid: 15313361
references.citation: Cell. 2012 Aug 17;150(4):780-91
references.pmid: 22863277
references.citation: Arthritis Rheum. 2006 Jun;54(6):1961-73
references.pmid: 16736506
references.citation: Int Rev Immunol. 2008;27(6):472-96
references.pmid: 19065352
references.citation: FASEB J. 2009 Sep;23(9):2968-77
references.pmid: 19395477
references.citation: J Innate Immun. 2012;4(1):6-15
references.pmid: 22086146
references.citation: Int J Mol Sci. 2012;13(7):8293-307
references.pmid: 22942703
references.citation: Nat Med. 2011 Dec 11;18(1):148-52
references.pmid: 22157678
references.citation: N Engl J Med. 2006 Jun 22;354(25):2667-76
references.pmid: 16790699
references.citation: Hepatology. 2010 Mar;51(3):1027-36
references.pmid: 20052656
references.citation: FEBS Open Bio. 2012 Mar 25;2:47-50
references.pmid: 23650580
references.citation: Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):16850-5
references.pmid: 24082095
references.citation: Arthritis Rheum. 1997 Mar;40(3):540-50
references.pmid: 9082943
references.citation: Arthritis Rheum. 2007 Dec;56(12):4203-15
references.pmid: 18050252
references.citation: Arthritis Rheum. 2011 Jun;63(6):1707-17
references.pmid: 21370225
references.citation: Arthritis Rheum. 2009 Sep;60(9):2822-9
references.pmid: 19714649
references.citation: Curr Opin Rheumatol. 2012 Nov;24(6):663-8
references.pmid: 22918530
references.citation: Curr Rheumatol Rep. 2012 Feb;14(1):30-8
references.pmid: 22006170
references.citation: J Exp Med. 2003 Oct 20;198(8):1179-88
references.pmid: 14557415
references.citation: Arthritis Rheum. 2010 Jun;62(6):1733-43
references.pmid: 20201077
references.citation: Curr Opin Rheumatol. 2011 Nov;23(6):505-10
references.pmid: 21885976
references.citation: J Clin Gastroenterol. 2007 Jul;41(6):616-23
references.pmid: 17577119
references.citation: Nat Rev Mol Cell Biol. 2001 Nov;2(11):793-805
references.pmid: 11715046
references.citation: Nat Rev Rheumatol. 2013 Aug;9(8):451-64
references.pmid: 23567456
references.citation: Curr Opin Rheumatol. 2013 Jan;25(1):92-100
references.pmid: 23114589
references.citation: PLoS One. 2012;7(10):e46512
references.pmid: 23056328
references.citation: Arthritis Rheum. 2011 May;63(5):1396-404
references.pmid: 21312186
references.citation: Nat Rev Rheumatol. 2010 Aug;6(8):453-60
references.pmid: 20585340
references.citation: Ann Rheum Dis. 2014 Feb;73(2):446-54
references.pmid: 23515440
references.citation: Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6065-9
references.pmid: 1385868
references.citation: J Invest Dermatol. 2005 Sep;125(3):421-7
references.pmid: 16117781
references.citation: Am J Respir Cell Mol Biol. 2002 Apr;26(4):484-90
references.pmid: 11919085
references.citation: Annu Rev Genet. 2012;46:165-83
references.pmid: 22934644
references.citation: Cytokine. 2011 Dec;56(3):544-9
references.pmid: 21920770
references.citation: Nat Cell Biol. 2008 Jul;10(7):837-48
references.pmid: 18568018
references.citation: Br J Dermatol. 1995 Nov;133(5):710-5
references.pmid: 8555021
references.citation: Curr Opin Rheumatol. 2012 Nov;24(6):649-55
references.pmid: 22810365
references.citation: Ann Rheum Dis. 2013 Jul;72(7):1217-20
references.pmid: 23253926
references.citation: Immunity. 2014 Jan 16;40(1):40-50
references.pmid: 24412616
references.citation: Rheumatology (Oxford). 2006 Oct;45 Suppl 3:iii23-5
references.pmid: 16987826
references.citation: J Invest Dermatol. 1991 Oct;97(4):686-92
references.pmid: 1940439
references.citation: Am J Respir Cell Mol Biol. 2009 Jun;40(6):654-62
references.pmid: 18988918
references.citation: J Clin Invest. 1994 Apr;93(4):1709-15
references.pmid: 7512991
references.citation: Autophagy. 2008 Feb;4(2):141-50
references.pmid: 17986870
references.citation: Arthritis Rheum. 1996 Aug;39(8):1338-46
references.pmid: 8702442
references.citation: Arthritis Rheum. 2008 Aug;58(8):2553-64
references.pmid: 18668558
references.citation: J Invest Dermatol. 2010 Nov;130(11):2583-93
references.pmid: 20613770
references.citation: Nature. 2011 Jun 08;474(7350):179-83
references.pmid: 21654799
references.citation: Clin Immunol Immunopathol. 1992 May;63(2):182-7
references.pmid: 1611720
references.citation: Curr Biol. 2001 May 15;11(10):764-8
references.pmid: 11378386
references.citation: Nephrol Dial Transplant. 2011 Sep;26(9):2770-9
references.pmid: 21378147
references.citation: Rheumatology (Oxford). 2012 Dec;51(12):2146-54
references.pmid: 22977060
references.citation: Nat Rev Cancer. 2012 Jul 19;12(8):540-52
references.pmid: 22810810
references.citation: Arthritis Rheum. 2012 Aug;64(8):2734-45
references.pmid: 22328118
references.citation: J Rheumatol. 2007 Apr;34(4):747-53
references.pmid: 17407232
references.citation: PLoS One. 2010 Nov 02;5(11):e13778
references.pmid: 21072170
references.citation: Clin Exp Rheumatol. 2013 Mar-Apr;31(2 Suppl 76):71-80
references.pmid: 23910613
references.citation: J Exp Med. 1997 Feb 3;185(3):461-9
references.pmid: 9053446
references.citation: J Mol Cell Cardiol. 2001 Jan;33(1):83-94
references.pmid: 11133225
references.citation: Am J Pathol. 2009 Feb;174(2):519-33
references.pmid: 19147827
references.citation: Self Nonself. 2011 Jan;2(1):4-10
references.pmid: 21776329
references.citation: Mol Biol Cell. 2003 Jun;14(6):2508-19
references.pmid: 12808047
references.citation: Nat Rev Rheumatol. 2011 Oct 25;8(1):42-54
references.pmid: 22025123
references.citation: Br J Pharmacol. 2012 Feb;165(4):829-44
references.pmid: 21838759
references.citation: J Cell Physiol. 2004 Mar;198(3):350-8
references.pmid: 14755540
references.citation: J Rheumatol. 1998 Feb;25(2):308-13
references.pmid: 9489824
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2827-30
references.pmid: 17307869
references.citation: Rheumatology (Oxford). 2001 Oct;40(10):1135-40
references.pmid: 11600743
references.citation: J Am Soc Nephrol. 2007 Dec;18(12):3110-8
references.pmid: 18003779
references.citation: J Clin Invest. 2013 Mar;123(3):1096-108
references.pmid: 23434591
references.citation: Am J Pathol. 2011 Dec;179(6):2751-65
references.pmid: 21983071
references.citation: Cell Tissue Res. 2011 Sep;345(3):391-403
references.pmid: 21858462
references.citation: Autoimmun Rev. 2007 Sep;6(8):520-3
references.pmid: 17854742
references.citation: J Cell Biol. 2010 Aug 23;190(4):693-706
references.pmid: 20733059
references.citation: Am J Respir Crit Care Med. 2011 Jan 15;183(2):249-61
references.pmid: 20709822
references.citation: Arthritis Rheum. 2012 May;64(5):1653-64
references.pmid: 22492165
references.citation: Curr Opin Rheumatol. 2004 Nov;16(6):723-32
references.pmid: 15577611
references.citation: Am J Pathol. 2013 Jan;182(1):206-16
references.pmid: 23159943
references.citation: Pathobiology. 1993;61(5-6):239-46
references.pmid: 7507681
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):E1475-83
references.pmid: 22123957
references.citation: Nat Cell Biol. 2000 Jun;2(6):326-32
references.pmid: 10854322
references.citation: Arthritis Rheum. 2002 Jun;46(6):1595-601
references.pmid: 12115191
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 8;105(27):9244-9
references.pmid: 18591668
references.citation: Nihon Rinsho Meneki Gakkai Kaishi. 2010;33(2):81-6
references.pmid: 20453443
references.citation: Arthritis Rheum. 2013 May;65(5):1357-66
references.pmid: 23400395
references.citation: Arthritis Res Ther. 2005;7(5):R1113-23
references.pmid: 16207328
references.citation: Curr Opin Rheumatol. 2014 Mar;26(2):131-7
references.pmid: 24441644
references.citation: Life Sci. 2007 Sep 1;81(12):1009-15
references.pmid: 17850827
references.citation: PLoS One. 2009 Jun 22;4(6):e5981
references.pmid: 19543397
references.citation: Bone. 2006 Oct;39(4):754-66
references.pmid: 16730481
references.citation: PLoS One. 2008 Jul 16;3(7):e2696
references.pmid: 18648520
references.citation: Clin Exp Immunol. 2004 Nov;138(2):357-63
references.pmid: 15498049
references.citation: Arthritis Rheum. 2009 Apr;60(4):1119-28
references.pmid: 19333920
references.citation: J Biol Chem. 2011 Dec 23;286(51):44116-44125
references.pmid: 22049076
references.citation: Curr Opin Investig Drugs. 2010 May;11(5):515-26
references.pmid: 20419597
references.citation: Nat Med. 2007 Aug;13(8):952-61
references.pmid: 17660828
references.citation: Cell Mol Life Sci. 2008 Jun;65(11):1683-97
references.pmid: 18327662
references.citation: Front Immunol. 2012 Aug 02;3:233
references.pmid: 22876246
references.citation: Arthritis Rheum. 2001 Jul;44(7):1667-76
references.pmid: 11465719
references.citation: Int J Med Sci. 2009 Jun 05;6(4):168-76
references.pmid: 19521548
references.citation: J Cell Mol Med. 2013 Apr;17(4):482-96
references.pmid: 23444845
references.citation: J Cardiovasc Pharmacol. 2007 Aug;50(2):187-94
references.pmid: 17703135
references.citation: J Rheumatol. 1997 Feb;24(2):328-32
references.pmid: 9034992
references.citation: Expert Opin Investig Drugs. 2010 Jun;19(6):777-88
references.pmid: 20465362
references.citation: Fibrogenesis Tissue Repair. 2011 Jun 02;4:13
references.pmid: 21635730
references.citation: J Cell Mol Med. 2009 Aug;13(8B):1644-1652
references.pmid: 18624756
references.citation: Arthritis Rheum. 2007 Jan;56(1):323-33
references.pmid: 17195236
references.citation: J Biol Chem. 2004 Oct 1;279(40):41783-91
references.pmid: 15271999
references.citation: Ann Rheum Dis. 2014 Jun;73(6):1215-22
references.pmid: 23661493
references.citation: Am J Pathol. 2010 Jan;176(1):85-97
references.pmid: 20008127
references.citation: Circ Res. 2010 Jul 23;107(2):294-304
references.pmid: 20558820
references.citation: Calcif Tissue Int. 2006 Dec;79(6):431-42
references.pmid: 17171500
references.citation: Arthritis Rheum. 1999 Jun;42(6):1168-78
references.pmid: 10366109
references.citation: PLoS One. 2009 Jul 09;4(7):e6203
references.pmid: 19587802
references.citation: J Cell Mol Med. 2012 Jul;16(7):1405-20
references.pmid: 22500885
references.citation: Ann Rheum Dis. 2011 Jul;70(7):1304-10
references.pmid: 21450749
references.citation: Nat Chem Biol. 2010 Nov;6(11):829-36
references.pmid: 20890287
references.citation: Cell Cycle. 2011 Jul 1;10(13):2140-50
references.pmid: 21670602
references.citation: Genes Dev. 2012 Jun 15;26(12):1300-5
references.pmid: 22677547
references.citation: Biochim Biophys Acta. 2013 Jul;1832(7):940-7
references.pmid: 23201247
references.citation: Int J Biochem Cell Biol. 2009 Aug-Sep;41(8-9):1708-18
references.pmid: 19433312
references.citation: J Immunol. 2013 Apr 15;190(8):3905-15
references.pmid: 23509348
references.citation: J Cell Mol Med. 2010 Oct;14(10):2531-8
references.pmid: 20977627
references.citation: J Exp Med. 2012 May 7;209(5):925-33
references.pmid: 22493518
references.citation: Lab Invest. 2012 Nov;92(11):1583-96
references.pmid: 22964853
references.citation: Histochem Cell Biol. 2008 Nov;130(5):979-92
references.pmid: 18633634
references.citation: Ann Rheum Dis. 1990 Jan;49(1):40-5
references.pmid: 2138008
references.citation: Discov Med. 2010 Aug;10(51):161-7
references.pmid: 20807477
references.citation: Nat Med. 2008 Jan;14(1):45-54
references.pmid: 18066075
references.citation: Nat Rev Immunol. 2004 Aug;4(8):583-94
references.pmid: 15286725
references.citation: FASEB J. 2013 May;27(5):1830-46
references.pmid: 23322166
references.citation: Am J Pathol. 2008 Dec;173(6):1617-27
references.pmid: 19008372
references.citation: Drugs. 2013 Mar;73(4):341-56
references.pmid: 23456676
references.citation: Clin Rev Allergy Immunol. 2011 Apr;40(2):78-83
references.pmid: 20143182
references.citation: Rheumatology (Oxford). 2010 Dec;49(12):2408-12
references.pmid: 20819796
references.citation: Scand J Rheumatol. 2009;38(4):282-90
references.pmid: 19255934
references.citation: Arthritis Rheum. 1984 Jun;27(6):645-53
references.pmid: 6375682
references.citation: Arthritis Rheum. 1999 May;42(5):930-41
references.pmid: 10323448
references.citation: J Surg Res. 2009 May 15;153(2):210-6
references.pmid: 18639247
references.citation: Arthritis Rheum. 2008 Dec;58(12):3913-23
references.pmid: 19035500
references.citation: J Immunol. 2007 Dec 1;179(11):7883-90
references.pmid: 18025235