Login Register Cart 0
Generic placeholder image

Current Molecular Medicine

Editor-in-Chief

ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Review Article

The Role of Pro-fibrotic Myofibroblasts in Systemic Sclerosis: From Origin to Therapeutic Targeting

Author(s): Eloisa Romano*, Irene Rosa, Bianca Saveria Fioretto, Marco Matucci-Cerinic and Mirko Manetti

Volume 22, Issue 3, 2022

Published on: 25 March, 2021

Page: [209 - 239] Pages: 31

DOI: 10.2174/0929867328666210325102749

Price: $65

Abstract

Systemic sclerosis (SSc, scleroderma) is a complex connective tissue disorder characterized by multisystem clinical manifestations resulting from immune dysregulation/autoimmunity, vasculopathy, and, most notably, progressive fibrosis of the skin and internal organs. In recent years, it has been observed that the main drivers of SSc-related tissue fibrosis are myofibroblasts, a type of mesenchymal cells with both the extracellular matrix-synthesizing features of fibroblasts and the cytoskeletal characteristics of contractile smooth muscle cells. The accumulation and persistent activation of pro-fibrotic myofibroblasts during SSc development and progression result in elevated mechanical stress and reduced matrix plasticity within the affected tissues and may be ascribed to a reduced susceptibility of these cells to pro-apoptotic stimuli, as well as their increased formation from tissue-resident fibroblasts or transition from different cell types. Given the crucial role of myofibroblasts in SSc pathogenesis, finding the way to inhibit myofibroblast differentiation and accumulation by targeting their formation, function, and survival may represent an effective approach to hamper the fibrotic process or even halt or reverse established fibrosis. In this review, we discuss the role of myofibroblasts in SSc-related fibrosis, with a special focus on their cellular origin and the signaling pathways implicated in their formation and persistent activation. Furthermore, we provide an overview of potential therapeutic strategies targeting myofibroblasts that may be able to counteract fibrosis in this pathological condition.

Keywords: Systemic sclerosis, scleroderma, fibrosis, myofibroblasts, signaling pathways, therapeutic targets.

« Previous Next »
[1]
Varga J, Trojanowska M, Kuwana M. Pathogenesis of systemic sclerosis: recent insights of molecular and cellular mechanisms and therapeutic opportunities. J Scleroderma Relat Disord 2017; 2(3): 137-52.
[http://dx.doi.org/10.5301/jsrd.5000249]
[2]
Denton CP, Khanna D. Systemic sclerosis. Lancet 2017; 390(10103): 1685-99.
[http://dx.doi.org/10.1016/S0140-6736(17)30933-9] [PMID: 28413064]
[3]
Sierra-Sepúlveda A, Esquinca-González A, Benavides-Suárez SA, et al. Systemic sclerosis sclerosis pathogenesis and emerging therapies, beyond the fibroblast. BioMed Res Int 2019; 2019: 4569826.
[http://dx.doi.org/10.1155/2019/4569826] [PMID: 30809542]
[4]
Korman B. Evolving insights into the cellular and molecular pathogenesis of fibrosis in systemic sclerosis. Transl Res 2019; 209: 77-89.
[http://dx.doi.org/10.1016/j.trsl.2019.02.010] [PMID: 30876809]
[5]
van Caam A, Vonk M, van den Hoogen F, van Lent P, van der Kraan P. Unraveling SSc pathophysiology; the myofibroblast. Front Immunol 2018; 9: 2452.
[http://dx.doi.org/10.3389/fimmu.2018.02452] [PMID: 30483246]
[6]
Hinz B, Phan SH, Thannickal VJ, et al. Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol 2012; 180(4): 1340-55.
[http://dx.doi.org/10.1016/j.ajpath.2012.02.004] [PMID: 22387320]
[7]
Hinz B. The role of myofibroblasts in wound healing. Curr Res Transl Med 2016; 64(4): 171-7.
[http://dx.doi.org/10.1016/j.retram.2016.09.003] [PMID: 27939455]
[8]
Leask A. Matrix remodeling in systemic sclerosis. Semin Immunopathol 2015; 37(5): 559-63.
[http://dx.doi.org/10.1007/s00281-015-0508-2] [PMID: 26141607]
[9]
Myofibroblasts HB. Exp Eye Res 2016; 142: 56-70.
[http://dx.doi.org/10.1016/j.exer.2015.07.009] [PMID: 26192991]
[10]
Mahmoudi MB, Farashahi Yazd E, Gharibdoost F, et al. Overexpression of apoptosis-related protein, survivin, in fibroblasts from patients with systemic sclerosis. Ir J Med Sci 2019; 188(4): 1443-9.
[http://dx.doi.org/10.1007/s11845-019-01978-w] [PMID: 30761457]
[11]
Leroy EC. Connective tissue synthesis by scleroderma skin fibroblasts in cell culture. J Exp Med 1972; 135(6): 1351-62.
[http://dx.doi.org/10.1084/jem.135.6.1351] [PMID: 4260235]
[12]
Sappino AP, Masouyé I, Saurat JH, Gabbiani G. Smooth muscle differentiation in scleroderma fibroblastic cells. Am J Pathol 1990; 137(3): 585-91.
[PMID: 1698026]
[13]
Kissin EY, Merkel PA, Lafyatis R. Myofibroblasts and hyalinized collagen as markers of skin disease in systemic sclerosis. Arthritis Rheum 2006; 54(11): 3655-60.
[http://dx.doi.org/10.1002/art.22186] [PMID: 17075814]
[14]
Ziemek J, Man A, Hinchcliff M, Varga J, Simms RW, Lafyatis R. The relationship between skin symptoms and the scleroderma modification of the health assessment questionnaire, the modified Rodnan skin score, and skin pathology in patients with systemic sclerosis. Rheumatology (Oxford) 2016; 55(5): 911-7.
[http://dx.doi.org/10.1093/rheumatology/kew003] [PMID: 26880832]
[15]
Van Praet JT, Smith V, Haspeslagh M, Degryse N, Elewaut D, De Keyser F. Histopathological cutaneous alterations in systemic sclerosis: a clinicopathological study. Arthritis Res Ther 2011; 13(1): R35.
[http://dx.doi.org/10.1186/ar3267] [PMID: 21356083]
[16]
Beon M, Harley RA, Wessels A, Silver RM, Ludwicka-Bradley A. Myofibroblast induction and microvascular alteration in scleroderma lung fibrosis. Clin Exp Rheumatol 2004; 22(6): 733-42.
[PMID: 15638048]
[17]
Ludwicka A, Trojanowska M, Smith EA, et al. Growth and characterization of fibroblasts obtained from bronchoalveolar lavage of patients with scleroderma. J Rheumatol 1992; 19(11): 1716-23.
[PMID: 1491389]
[18]
Manetti M, Neumann E, Milia AF, et al. Severe fibrosis and increased expression of fibrogenic cytokines in the gastric wall of systemic sclerosis patients. Arthritis Rheum 2007; 56(10): 3442-7.
[http://dx.doi.org/10.1002/art.22940] [PMID: 17907149]
[19]
Gilbane AJ, Denton CP, Holmes AM. Scleroderma pathogenesis: a pivotal role for fibroblasts as effector cells. Arthritis Res Ther 2013; 15(3): 215.
[http://dx.doi.org/10.1186/ar4230] [PMID: 23796020]
[20]
Moulin V, Larochelle S, Langlois C, Thibault I, Lopez-Vallé CA, Roy M. Normal skin wound and hypertrophic scar myofibroblasts have differential responses to apoptotic inductors. J Cell Physiol 2004; 198(3): 350-8.
[http://dx.doi.org/10.1002/jcp.10415] [PMID: 14755540]
[21]
Desmoulière A, Redard M, Darby I, Gabbiani G. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol 1995; 146(1): 56-66.
[PMID: 7856739]
[22]
Hinz B, Lagares D. Evasion of apoptosis by myofibroblasts: a hallmark of fibrotic diseases. Nat Rev Rheumatol 2020; 16(1): 11-31.
[http://dx.doi.org/10.1038/s41584-019-0324-5] [PMID: 31792399]
[23]
Kuehl T, Lagares D. BH3 mimetics as anti-fibrotic therapy: Unleashing the mitochondrial pathway of apoptosis in myofibroblasts. Matrix Biol 2018; 68-69: 94-105.
[http://dx.doi.org/10.1016/j.matbio.2018.01.020] [PMID: 29408011]
[24]
Horowitz JC, Lee DY, Waghray M, et al. Activation of the pro-survival phosphatidylinositol 3-kinase/AKT pathway by transforming growth factor-beta1 in mesenchymal cells is mediated by p38 MAPK-dependent induction of an autocrine growth factor. J Biol Chem 2004; 279(2): 1359-67.
[http://dx.doi.org/10.1074/jbc.M306248200] [PMID: 14576166]
[25]
Jun JB, Kuechle M, Min J, et al. Scleroderma fibroblasts demonstrate enhanced activation of Akt (protein kinase B) in situ. J Invest Dermatol 2005; 124(2): 298-303.
[http://dx.doi.org/10.1111/j.0022-202X.2004.23559.x] [PMID: 15675946]
[26]
Jelaska A, Korn JH. Role of apoptosis and transforming growth factor beta1 in fibroblast selection and activation in systemic sclerosis. Arthritis Rheum 2000; 43(10): 2230-9.
[http://dx.doi.org/10.1002/1529-0131(200010)43:10<2230:AID-ANR10>3.0.CO;2-8] [PMID: 11037882]
[27]
Santiago B, Galindo M, Rivero M, Pablos JL. Decreased susceptibility to Fas-induced apoptosis of systemic sclerosis dermal fibroblasts. Arthritis Rheum 2001; 44(7): 1667-76.
[http://dx.doi.org/10.1002/1529-0131(200107)44:7<1667:AID-ART291>3.0.CO;2-Y] [PMID: 11465719]
[28]
Samuel GH, Lenna S, Bujor AM, Lafyatis R, Trojanowska M. Acid sphingomyelinase deficiency contributes to resistance of scleroderma fibroblasts to Fas-mediated apoptosis. J Dermatol Sci 2012; 67(3): 166-72.
[http://dx.doi.org/10.1016/j.jdermsci.2012.06.001] [PMID: 22771321]
[29]
Karimizadeh E, Gharibdoost F, Motamed N, Jafarinejad-Farsangi S, Jamshidi A, Mahmoudi M. c-Abl silencing reduced the inhibitory effects of TGF-β1 on apoptosis in systemic sclerosis dermal fibroblasts. Mol Cell Biochem 2015; 405(1-2): 169-76.
[http://dx.doi.org/10.1007/s11010-015-2408-0] [PMID: 25876876]
[30]
Lagares D, Santos A, Grasberger PE, et al. Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis. Sci Transl Med 2017; 9(420): aal3765.
[http://dx.doi.org/10.1126/scitranslmed.aal3765] [PMID: 29237758]
[31]
Jafarinejad-Farsangi S, Farazmand A, Gharibdoost F, et al. Inhibition of MicroRNA-21 induces apoptosis in dermal fibroblasts of patients with systemic sclerosis. Int J Dermatol 2016; 55(11): 1259-67.
[http://dx.doi.org/10.1111/ijd.13308] [PMID: 27637490]
[32]
Liu Y, Li Y, Li N, et al. TGF-β1 promotes scar fibroblasts proliferation and transdifferentiation via up-regulating MicroRNA-21. Sci Rep 2016; 6: 32231.
[http://dx.doi.org/10.1038/srep32231] [PMID: 27554193]
[33]
Rosa I, Romano E, Fioretto BS, Manetti M. The contribution of mesenchymal transitions to the pathogenesis of systemic sclerosis. Eur J Rheumatol 2020; 7(Suppl. 3): S157-64.
[http://dx.doi.org/10.5152/eurjrheum.2019.19081] [PMID: 31922472]
[34]
Rajkumar VS, Howell K, Csiszar K, Denton CP, Black CM, Abraham DJ. Shared expression of phenotypic markers in systemic sclerosis indicates a convergence of pericytes and fibroblasts to a myofibroblast lineage in fibrosis. Arthritis Res Ther 2005; 7(5): R1113-23.
[http://dx.doi.org/10.1186/ar1790] [PMID: 16207328]
[35]
Dulauroy S, Di Carlo SE, Langa F, Eberl G, Peduto L. Lineage tracing and genetic ablation of ADAM12(+) perivascular cells identify a major source of profibrotic cells during acute tissue injury. Nat Med 2012; 18(8): 1262-70.
[http://dx.doi.org/10.1038/nm.2848] [PMID: 22842476]
[36]
Hung C, Linn G, Chow YH, et al. Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med 2013; 188(7): 820-30.
[http://dx.doi.org/10.1164/rccm.201212-2297OC] [PMID: 23924232]
[37]
Liu S, Taghavi R, Leask A. Connective tissue growth factor is induced in bleomycin-induced skin scleroderma. J Cell Commun Signal 2010; 4(1): 25-30.
[http://dx.doi.org/10.1007/s12079-009-0081-3] [PMID: 19916059]
[38]
Hung CF, Wilson CL, Chow YH, Schnapp LM. Role of integrin alpha8 in murine model of lung fibrosis. PLoS One 2018; 13(5): e0197937.
[http://dx.doi.org/10.1371/journal.pone.0197937] [PMID: 29813125]
[39]
Juniantito V, Izawa T, Yuasa T, et al. Immunophenotypical analysis of myofibroblasts and mesenchymal cells in the bleomycin-induced rat scleroderma, with particular reference to their origin. Exp Toxicol Pathol 2013; 65(5): 567-77.
[http://dx.doi.org/10.1016/j.etp.2012.05.002] [PMID: 22749686]
[40]
Ebmeier S, Horsley V. Origin of fibrosing cells in systemic sclerosis. Curr Opin Rheumatol 2015; 27(6): 555-62.
[http://dx.doi.org/10.1097/BOR.0000000000000217] [PMID: 26352735]
[41]
Cipriani P, Marrelli A, Benedetto PD, et al. Scleroderma Mesenchymal Stem Cells display a different phenotype from healthy controls; implications for regenerative medicine. Angiogenesis 2013; 16(3): 595-607.
[http://dx.doi.org/10.1007/s10456-013-9338-9] [PMID: 23413114]
[42]
Cipriani P, Di Benedetto P, Ruscitti P, et al. Perivascular cells in diffuse cutaneous systemic sclerosis overexpress activated ADAM12 and are involved in myofibroblast transdifferentiation and development of fibrosis. J Rheumatol 2016; 43(7): 1340-9.
[http://dx.doi.org/10.3899/jrheum.150996] [PMID: 27252423]
[43]
Hegner B, Schaub T, Catar R, et al. Intrinsic deregulation of vascular smooth muscle and myofibroblast differentiation in mesenchymal stromal cells from patients with systemic sclerosis. PLoS One 2016; 11(4): e0153101.
[http://dx.doi.org/10.1371/journal.pone.0153101] [PMID: 27054717]
[44]
Santos F, Moreira C, Nóbrega-Pereira S, Bernardes de Jesus B. New insights into the role of epithelial mesenchymal transition during aging. Int J Mol Sci 2019; 20(4): E891.
[http://dx.doi.org/10.3390/ijms20040891] [PMID: 30791369]
[45]
Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 2014; 15(3): 178-96.
[http://dx.doi.org/10.1038/nrm3758] [PMID: 24556840]
[46]
Piera-Velazquez S, Li Z, Jimenez SA. Role of endothelial-mesenchymal transition (EndoMT) in the pathogenesis of fibrotic disorders. Am J Pathol 2011; 179(3): 1074-80.
[http://dx.doi.org/10.1016/j.ajpath.2011.06.001] [PMID: 21763673]
[47]
Nikitorowicz-Buniak J, Denton CP, Abraham D, Stratton R. Partially evoked epithelial-mesenchymal transition (EMT) is associated with increased TGFbeta signaling within lesional scleroderma skin. PLoS One 2015; 10(7): e0134092.
[http://dx.doi.org/10.1371/journal.pone.0134092] [PMID: 26217927]
[48]
Kanno Y. The role of fibrinolytic regulators in vascular dysfunction of systemic sclerosis. Int J Mol Sci 2019; 20(3): E619.
[http://dx.doi.org/10.3390/ijms20030619] [PMID: 30709025]
[49]
Thuan DTB, Zayed H, Eid AH, et al. A potential link between oxidative stress and endothelial-to-mesenchymal transition in systemic sclerosis. Front Immunol 2018; 9: 1985.
[http://dx.doi.org/10.3389/fimmu.2018.01985] [PMID: 30283435]
[50]
Manetti M, Romano E, Rosa I, et al. Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis. Ann Rheum Dis 2017; 76(5): 924-34.
[http://dx.doi.org/10.1136/annrheumdis-2016-210229] [PMID: 28062404]
[51]
Nicolosi PA, Tombetti E, Maugeri N, Rovere-Querini P, Brunelli S, Manfredi AA. Vascular remodelling and mesenchymal transition in systemic sclerosis. Stem Cells Int 2016; 2016: 4636859.
[http://dx.doi.org/10.1155/2016/4636859] [PMID: 27069480]
[52]
Manetti M, Guiducci S, Matucci-Cerinic M. The origin of the myofibroblast in fibroproliferative vasculopathy: does the endothelial cell steer the pathophysiology of systemic sclerosis? Arthritis Rheum 2011; 63(8): 2164-7.
[http://dx.doi.org/10.1002/art.30316] [PMID: 21425121]
[53]
Jimenez SA, Piera-Velazquez S. Endothelial to mesenchymal transition (EndoMT) in the pathogenesis of Systemic Sclerosis-associated pulmonary fibrosis and pulmonary arterial hypertension. Myth or reality? Matrix Biol 2016; 51: 26-36.
[http://dx.doi.org/10.1016/j.matbio.2016.01.012] [PMID: 26807760]
[54]
Mendoza FA, Piera-Velazquez S, Farber JL, Feghali-Bostwick C, Jiménez SA. Endothelial cells expressing endothelial and mesenchymal cell gene products in lung tissue from patients with systemic sclerosis-associated interstitial lung disease. Arthritis Rheumatol 2016; 68(1): 210-7.
[http://dx.doi.org/10.1002/art.39421] [PMID: 26360820]
[55]
Good RB, Gilbane AJ, Trinder SL, et al. Endothelial to mesenchymal transition contributes to endothelial dysfunction in pulmonary arterial hypertension. Am J Pathol 2015; 185(7): 1850-8.
[http://dx.doi.org/10.1016/j.ajpath.2015.03.019] [PMID: 25956031]
[56]
Del Papa N, Pignataro F. The role of endothelial progenitors in the repair of vascular damage in systemic sclerosis. Front Immunol 2018; 9: 1383.
[http://dx.doi.org/10.3389/fimmu.2018.01383] [PMID: 29967618]
[57]
Patschan S, Tampe D, Müller C, et al. Early Endothelial Progenitor Cells (eEPCs) in systemic sclerosis (SSc) - dynamics of cellular regeneration and mesenchymal transdifferentiation. BMC Musculoskelet Disord 2016; 17: 339.
[http://dx.doi.org/10.1186/s12891-016-1197-2] [PMID: 27519706]
[58]
Marangoni RG, Korman BD, Wei J, et al. Myofibroblasts in murine cutaneous fibrosis originate from adiponectin-positive intradermal progenitors. Arthritis Rheumatol 2015; 67(4): 1062-73.
[http://dx.doi.org/10.1002/art.38990] [PMID: 25504959]
[59]
Marangoni RG, Lu TT. The roles of dermal white adipose tissue loss in scleroderma skin fibrosis. Curr Opin Rheumatol 2017; 29(6): 585-90.
[http://dx.doi.org/10.1097/BOR.0000000000000437] [PMID: 28800024]
[60]
Kruglikov IL, Scherer PE. Dermal adipocytes: from irrelevance to metabolic targets? Trends Endocrinol Metab 2016; 27(1): 1-10.
[http://dx.doi.org/10.1016/j.tem.2015.11.002] [PMID: 26643658]
[61]
Lee R, Del Papa N, Introna M, et al. Adipose-derived mesenchymal stromal/stem cells in systemic sclerosis: alterations in function and beneficial effect on lung fibrosis are regulated by caveolin-1. J Scleroderma Relat Disord 2019; 4: 127-36.
[http://dx.doi.org/10.1177/2397198318821510]
[62]
Manetti M, Romano E, Rosa I, et al. Systemic sclerosis serum steers the differentiation of adipose-derived stem cells toward profibrotic myofibroblasts: pathophysiologic implications. J Clin Med 2019; 8(8): 1256.
[http://dx.doi.org/10.3390/jcm8081256] [PMID: 31430950]
[63]
Wang YY, Jiang H, Pan J, et al. Macrophage-to-myofibroblast transition contributes to interstitial fibrosis in chronic renal allograft injury. J Am Soc Nephrol 2017; 28(7): 2053-67.
[http://dx.doi.org/10.1681/ASN.2016050573] [PMID: 28209809]
[64]
Tourkina E, Bonner M, Oates J, et al. Altered monocyte and fibrocyte phenotype and function in scleroderma interstitial lung disease: reversal by caveolin-1 scaffolding domain peptide. Fibrogenesis Tissue Repair 2011; 4(1): 15.
[http://dx.doi.org/10.1186/1755-1536-4-15] [PMID: 21722364]
[65]
Binai N, O’Reilly S, Griffiths B, van Laar JM, Hügle T. Differentiation potential of CD14+ monocytes into myofibroblasts in patients with systemic sclerosis. PLoS One 2012; 7(3): e33508.
[http://dx.doi.org/10.1371/journal.pone.0033508] [PMID: 22432031]
[66]
Piersma B, Bank RA, Boersema M. Signaling in fibrosis: TGF-β, WNT, and YAP/TAZ converge. Front Med (Lausanne) 2015; 2: 59.
[http://dx.doi.org/10.3389/fmed.2015.00059] [PMID: 26389119]
[67]
Stempien-Otero A, Kim DH, Davis J. Molecular networks underlying myofibroblast fate and fibrosis. J Mol Cell Cardiol 2016; 97: 153-61.
[http://dx.doi.org/10.1016/j.yjmcc.2016.05.002] [PMID: 27167848]
[68]
Dees C, Chakraborty D, Distler JHW. Cellular and molecular mechanisms in fibrosis. Exp Dermatol 2020.
[PMID: 32931037]
[69]
Robertson IB, Rifkin DB. Regulation of the Bioavailability of TGF-β and TGF-β-Related Proteins. Cold Spring Harb Perspect Biol 2016; 8(6): a021907.
[http://dx.doi.org/10.1101/cshperspect.a021907] [PMID: 27252363]
[70]
Hinz B. Tissue stiffness, latent TGF-beta1 activation, and mechanical signal transduction: implications for the pathogenesis and treatment of fibrosis. Curr Rheumatol Rep 2009; 11(2): 120-6.
[http://dx.doi.org/10.1007/s11926-009-0017-1] [PMID: 19296884]
[71]
Conroy KP, Kitto LJ, Henderson NC. αv integrins: key regulators of tissue fibrosis. Cell Tissue Res 2016; 365(3): 511-9.
[http://dx.doi.org/10.1007/s00441-016-2407-9] [PMID: 27139180]
[72]
Asano Y, Ihn H, Yamane K, Jinnin M, Mimura Y, Tamaki K. Involvement of alphavbeta5 integrin-mediated activation of latent transforming growth factor beta1 in autocrine transforming growth factor beta signaling in systemic sclerosis fibroblasts. Arthritis Rheum 2005; 52(9): 2897-905.
[http://dx.doi.org/10.1002/art.21246] [PMID: 16142753]
[73]
Asano Y, Ihn H, Yamane K, Jinnin M, Tamaki K. Increased expression of integrin alphavbeta5 induces the myofibroblastic differentiation of dermal fibroblasts. Am J Pathol 2006; 168(2): 499-510.
[http://dx.doi.org/10.2353/ajpath.2006.041306] [PMID: 16436664]
[74]
Horan GS, Wood S, Ona V, et al. Partial inhibition of integrin alpha(v)beta6 prevents pulmonary fibrosis without exacerbating inflammation. Am J Respir Crit Care Med 2008; 177(1): 56-65.
[http://dx.doi.org/10.1164/rccm.200706-805OC] [PMID: 17916809]
[75]
Sonnylal S, Denton CP, Zheng B, et al. Postnatal induction of transforming growth factor beta signaling in fibroblasts of mice recapitulates clinical, histologic, and biochemical features of scleroderma. Arthritis Rheum 2007; 56(1): 334-44.
[http://dx.doi.org/10.1002/art.22328] [PMID: 17195237]
[76]
Lafyatis R. Transforming growth factor β--at the centre of systemic sclerosis. Nat Rev Rheumatol 2014; 10(12): 706-19.
[http://dx.doi.org/10.1038/nrrheum.2014.137] [PMID: 25136781]
[77]
Li M, Krishnaveni MS, Li C, et al. Epithelium-specific deletion of TGF-β receptor type II protects mice from bleomycin-induced pulmonary fibrosis. J Clin Invest 2011; 121(1): 277-87.
[http://dx.doi.org/10.1172/JCI42090] [PMID: 21135509]
[78]
Wang Y, Fan PS, Kahaleh B. Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts. Arthritis Rheum 2006; 54(7): 2271-9.
[http://dx.doi.org/10.1002/art.21948] [PMID: 16802366]
[79]
Asano Y, Czuwara J, Trojanowska M. Transforming growth factor-beta regulates DNA binding activity of transcription factor Fli1 by p300/CREB-binding protein-associated factor-dependent acetylation. J Biol Chem 2007; 282(48): 34672-83.
[http://dx.doi.org/10.1074/jbc.M703907200] [PMID: 17884818]
[80]
Asano Y, Bujor AM, Trojanowska M. The impact of Fli1 deficiency on the pathogenesis of systemic sclerosis. J Dermatol Sci 2010; 59(3): 153-62.
[http://dx.doi.org/10.1016/j.jdermsci.2010.06.008] [PMID: 20663647]
[81]
Hsu HS, Liu CC, Lin JH, et al. Involvement of ER stress, PI3K/AKT activation, and lung fibroblast proliferation in bleomycin-induced pulmonary fibrosis. Sci Rep 2017; 7(1): 14272.
[http://dx.doi.org/10.1038/s41598-017-14612-5] [PMID: 29079731]
[82]
Pattanaik D, Brown M, Postlethwaite BC, Postlethwaite AE. Pathogenesis of systemic sclerosis. Front Immunol 2015; 6: 272.
[http://dx.doi.org/10.3389/fimmu.2015.00272] [PMID: 26106387]
[83]
Fang F, Ooka K, Bhattacharyya S, et al. The 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 responses. Am J Pathol 2011; 178(5): 2077-90.
[http://dx.doi.org/10.1016/j.ajpath.2011.01.035] [PMID: 21514423]
[84]
Chen SJ, Ning H, Ishida W, et al. The early-immediate gene EGR-1 is induced by transforming growth factor-beta and mediates stimulation of collagen gene expression. J Biol Chem 2006; 281(30): 21183-97.
[http://dx.doi.org/10.1074/jbc.M603270200] [PMID: 16702209]
[85]
Wu M, Melichian DS, de la Garza M, et al. Essential roles for early growth response transcription factor Egr-1 in tissue fibrosis and wound healing. Am J Pathol 2009; 175(3): 1041-55.
[http://dx.doi.org/10.2353/ajpath.2009.090241] [PMID: 19679873]
[86]
Bhattacharyya S, Sargent JL, Du P, et al. Egr-1 induces a profibrotic injury/repair gene program associated with systemic sclerosis. PLoS One 2011; 6(9): e23082.
[http://dx.doi.org/10.1371/journal.pone.0023082] [PMID: 21931594]
[87]
Bhattacharyya S, Fang F, Tourtellotte W, Varga J. Egr-1: new conductor for the tissue repair orchestra directs harmony (regeneration) or cacophony (fibrosis). J Pathol 2013; 229(2): 286-9.
[88]
Fang F, Shangguan AJ, Kelly K, et al. Early growth response 3 (Egr-3) is induced by transforming growth factor-β and regulates fibrogenic responses. Am J Pathol 2013; 183(4): 1197-208.
[http://dx.doi.org/10.1016/j.ajpath.2013.06.016] [PMID: 23906810]
[89]
Sacchetti C, Bai Y, Stanford SM, et al. PTP4A1 promotes TGFβ signaling and fibrosis in systemic sclerosis. Nat Commun 2017; 8(1): 1060.
[http://dx.doi.org/10.1038/s41467-017-01168-1] [PMID: 29057934]
[90]
Yamakage A, Kikuchi K, Smith EA, LeRoy EC, Trojanowska M. Selective upregulation of platelet-derived growth factor alpha receptors by transforming growth factor beta in scleroderma fibroblasts. J Exp Med 1992; 175(5): 1227-34.
[http://dx.doi.org/10.1084/jem.175.5.1227] [PMID: 1314885]
[91]
Zhao XK, Cheng Y, Liang Cheng M, et al. Focal adhesion kinase regulates fibroblast migration via integrin beta-1 and plays a central role in fibrosis. Sci Rep 2016; 6: 19276.
[http://dx.doi.org/10.1038/srep19276] [PMID: 26763945]
[92]
Carvalheiro T, Malvar Fernández B, Ottria A, et al. Extracellular SPARC cooperates with TGF-β signalling to induce pro-fibrotic activation of systemic sclerosis patient dermal fibroblasts. Rheumatology (Oxford) 2020; 59(9): 2258-63.
[http://dx.doi.org/10.1093/rheumatology/kez583] [PMID: 31840182]
[93]
Wei J, Marangoni RG, Fang F, et al. The non-neuronal cyclin-dependent kinase 5 is a fibrotic mediator potentially implicated in systemic sclerosis and a novel therapeutic target. Oncotarget 2017; 9(12): 10294-306.
[http://dx.doi.org/10.18632/oncotarget.23516] [PMID: 29535807]
[94]
Tomcik M, Palumbo-Zerr K, Zerr P, et al. Tribbles homologue 3 stimulates canonical TGF-β signalling to regulate fibroblast activation and tissue fibrosis. Ann Rheum Dis 2016; 75(3): 609-16.
[http://dx.doi.org/10.1136/annrheumdis-2014-206234] [PMID: 25603829]
[95]
Serratì S, Chillà A, Laurenzana A, et al. Systemic sclerosis endothelial cells recruit and activate dermal fibroblasts by induction of a connective tissue growth factor (CCN2)/transforming growth factor β-dependent mesenchymal-to-mesenchymal transition. Arthritis Rheum 2013; 65(1): 258-69.
[http://dx.doi.org/10.1002/art.37705] [PMID: 22972461]
[96]
Nakamura M, Tokura Y. Expression of SNAI1 and TWIST1 in the eccrine glands of patients with systemic sclerosis: possible involvement of epithelial-mesenchymal transition in the pathogenesis. Br J Dermatol 2011; 164(1): 204-5.
[http://dx.doi.org/10.1111/j.1365-2133.2010.10021.x] [PMID: 21054330]
[97]
Takahashi T, Asano Y, Sugawara K, et al. Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: Possible roles in scleroderma. J Exp Med 2017; 214(4): 1129-51.
[http://dx.doi.org/10.1084/jem.20160247] [PMID: 28232470]
[98]
McCoy SS, Reed TJ, Berthier CC, et al. Scleroderma keratinocytes promote fibroblast activation independent of transforming growth factor beta. Rheumatology (Oxford) 2017; 56(11): 1970-81.
[http://dx.doi.org/10.1093/rheumatology/kex280] [PMID: 28968684]
[99]
Jimenez SA. Role of endothelial to mesenchymal transition in the pathogenesis of the vascular alterations in systemic sclerosis. ISRN Rheumatol 2013; 2013: 835948.
[http://dx.doi.org/10.1155/2013/835948] [PMID: 24175099]
[100]
Wermuth PJ, Carney KR, Mendoza FA, Piera-Velazquez S, Jimenez SA. Endothelial cell-specific activation of transforming growth factor-β signaling in mice induces cutaneous, visceral, and microvascular fibrosis. Lab Invest 2017; 97(7): 806-18.
[http://dx.doi.org/10.1038/labinvest.2017.23] [PMID: 28346399]
[101]
Taniguchi T, Asano Y, Akamata K, et al. Fibrosis, vascular activation, and immune abnormalities resembling systemic sclerosis in bleomycin-treated Fli-1-haploinsufficient mice. Arthritis Rheumatol 2015; 67(2): 517-26.
[http://dx.doi.org/10.1002/art.38948] [PMID: 25385187]
[102]
Manetti M. Fli1 deficiency and beyond: a unique pathway linking peripheral vasculopathy and dermal fibrosis in systemic sclerosis. Exp Dermatol 2015; 24(4): 256-7.
[http://dx.doi.org/10.1111/exd.12619] [PMID: 25529866]
[103]
Asano Y, Stawski L, Hant F, et al. Endothelial Fli1 deficiency impairs vascular homeostasis: a role in scleroderma vasculopathy. Am J Pathol 2010; 176(4): 1983-98.
[http://dx.doi.org/10.2353/ajpath.2010.090593] [PMID: 20228226]
[104]
Abe R, Donnelly SC, Peng T, Bucala R, Metz CN. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J Immunol 2001; 166(12): 7556-62.
[http://dx.doi.org/10.4049/jimmunol.166.12.7556] [PMID: 11390511]
[105]
Sun H, Zhu Y, Pan H, et al. Netrin-1 regulates fibrocyte accumulation in the decellularized fibrotic sclerodermatous lung microenvironment and in bleomycin-induced pulmonary fibrosis. Arthritis Rheumatol 2016; 68(5): 1251-61.
[PMID: 26749424]
[106]
Beyer C, Distler JH. Morphogen pathways in systemic sclerosis. Curr Rheumatol Rep 2013; 15(1): 299.
[http://dx.doi.org/10.1007/s11926-012-0299-6] [PMID: 23292815]
[107]
Gyftaki-Venieri DA, Abraham DJ, Ponticos M. Insights into myofibroblasts and their activation in scleroderma: opportunities for therapy? Curr Opin Rheumatol 2018; 30(6): 581-7.
[http://dx.doi.org/10.1097/BOR.0000000000000543] [PMID: 30074511]
[108]
Cisternas P, Vio CP, Inestrosa NC. Role of Wnt signaling in tissue fibrosis, lessons from skeletal muscle and kidney. Curr Mol Med 2014; 14(4): 510-22.
[http://dx.doi.org/10.2174/1566524014666140414210346] [PMID: 24730522]
[109]
Wild SL, Elghajiji A, Grimaldos Rodriguez C, Weston SD, Burke ZD, Tosh D. The canonical Wnt pathway as a key regulator in liver development, differentiation and homeostatic renewal. Genes (Basel) 2020; 11(10): E1163.
[http://dx.doi.org/10.3390/genes11101163] [PMID: 33008122]
[110]
Wei J, Fang F, Lam AP, et al. Wnt/β-catenin signaling is hyperactivated in systemic sclerosis and induces Smad-dependent fibrotic responses in mesenchymal cells. Arthritis Rheum 2012; 64(8): 2734-45.
[http://dx.doi.org/10.1002/art.34424] [PMID: 22328118]
[111]
Wei J, Melichian D, Komura K, et al. Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: a novel mouse model for scleroderma? Arthritis Rheum 2011; 63(6): 1707-17.
[http://dx.doi.org/10.1002/art.30312] [PMID: 21370225]
[112]
Akhmetshina A, Palumbo K, Dees C, et al. Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis. Nat Commun 2012; 3: 735.
[http://dx.doi.org/10.1038/ncomms1734] [PMID: 22415826]
[113]
Beyer C, Schramm A, Akhmetshina A, et al. β-catenin is a central mediator of pro-fibrotic Wnt signaling in systemic sclerosis. Ann Rheum Dis 2012; 71(5): 761-7.
[http://dx.doi.org/10.1136/annrheumdis-2011-200568] [PMID: 22328737]
[114]
Dees C, Schlottmann I, Funke R, et al. The Wnt antagonists DKK1 and SFRP1 are downregulated by promoter hypermethylation in systemic sclerosis. Ann Rheum Dis 2014; 73(6): 1232-9.
[http://dx.doi.org/10.1136/annrheumdis-2012-203194] [PMID: 23698475]
[115]
Henderson J, Pryzborski S, Stratton R, O’Reilly S. Wnt antagonist DKK-1 levels in systemic sclerosis are lower in skin but not in blood and are regulated by microRNA33a-3p. Exp Dermatol 2020.
[PMID: 32592422]
[116]
Larsen LJ, Møller LB. Crosstalk of Hedgehog and mTORC1 Pathways. Cells 2020; 9(10): E2316.
[http://dx.doi.org/10.3390/cells9102316] [PMID: 33081032]
[117]
Skoda AM, Simovic D, Karin V, Kardum V, Vranic S, Serman L. The role of the Hedgehog signaling pathway in cancer: A comprehensive review. Bosn J Basic Med Sci 2018; 18(1): 8-20.
[http://dx.doi.org/10.17305/bjbms.2018.2756] [PMID: 29274272]
[118]
Horn A, Kireva T, Palumbo-Zerr K, et al. Inhibition of hedgehog signalling prevents experimental fibrosis and induces regression of established fibrosis. Ann Rheum Dis 2012; 71(5): 785-9.
[http://dx.doi.org/10.1136/annrheumdis-2011-200883] [PMID: 22402139]
[119]
Zerr P, Palumbo-Zerr K, Distler A, et al. Inhibition of hedgehog signaling for the treatment of murine sclerodermatous chronic graft-versus-host disease. Blood 2012; 120(14): 2909-17.
[http://dx.doi.org/10.1182/blood-2012-01-403428] [PMID: 22915638]
[120]
Liang R, Šumová B, Cordazzo C, et al. The transcription factor GLI2 as a downstream mediator of transforming growth factor-β-induced fibroblast activation in SSc. Ann Rheum Dis 2017; 76(4): 756-64.
[http://dx.doi.org/10.1136/annrheumdis-2016-209698] [PMID: 27793816]
[121]
Horn A, Palumbo K, Cordazzo C, et al. Hedgehog signaling controls fibroblast activation and tissue fibrosis in systemic sclerosis. Arthritis Rheum 2012; 64(8): 2724-33.
[http://dx.doi.org/10.1002/art.34444] [PMID: 22354771]
[122]
Liang R, Kagwiria R, Zehender A, et al. Acyltransferase skinny hedgehog regulates TGFβ-dependent fibroblast activation in SSc. Ann Rheum Dis 2019; 78(9): 1269-73.
[http://dx.doi.org/10.1136/annrheumdis-2019-215066] [PMID: 31177096]
[123]
Beyer C, Huscher D, Ramming A, et al. Elevated serum levels of sonic hedgehog are associated with fibrotic and vascular manifestations in systemic sclerosis. Ann Rheum Dis 2018; 77(4): 626-8.
[http://dx.doi.org/10.1136/annrheumdis-2016-210834] [PMID: 28495672]
[124]
Dees C, Tomcik M, Zerr P, et al. Notch signalling regulates fibroblast activation and collagen release in systemic sclerosis. Ann Rheum Dis 2011; 70(7): 1304-10.
[http://dx.doi.org/10.1136/ard.2010.134742]
[125]
Kavian N, Servettaz A, Mongaret C, et al. Targeting ADAM-17/notch signaling abrogates the development of systemic sclerosis in a murine model. Arthritis Rheum 2010; 62(11): 3477-87.
[http://dx.doi.org/10.1002/art.27626] [PMID: 20583103]
[126]
Dees C, Zerr P, Tomcik M, et al. Inhibition of Notch signaling prevents experimental fibrosis and induces regression of established fibrosis. Arthritis Rheum 2011; 63(5): 1396-404.
[http://dx.doi.org/10.1002/art.30254] [PMID: 21312186]
[127]
Martins V, Gonzalez De Los Santos F, Wu Z, Capelozzi V, Phan SH, Liu T. FIZZ1-induced myofibroblast transdifferentiation from adipocytes and its potential role in dermal fibrosis and lipoatrophy. Am J Pathol 2015; 185(10): 2768-76.
[http://dx.doi.org/10.1016/j.ajpath.2015.06.005] [PMID: 26261086]
[128]
Liu T, Yu H, Ullenbruch M, et al. The in vivo fibrotic role of FIZZ1 in pulmonary fibrosis. PLoS One 2014; 9(2): e88362.
[http://dx.doi.org/10.1371/journal.pone.0088362] [PMID: 24516640]
[129]
Wasson CW, Abignano G, Hermes H, et al. Long non-coding RNA HOTAIR drives EZH2-dependent myofibroblast activation in systemic sclerosis through miRNA 34a-dependent activation of NOTCH. Ann Rheum Dis 2020; 79(4): 507-17.
[http://dx.doi.org/10.1136/annrheumdis-2019-216542] [PMID: 32041748]
[130]
Liu F, Lagares D, Choi KM, et al. Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis. Am J Physiol Lung Cell Mol Physiol 2015; 308(4): L344-57.
[http://dx.doi.org/10.1152/ajplung.00300.2014] [PMID: 25502501]
[131]
Dupont S, Morsut L, Aragona M, et al. Role of YAP/TAZ in mechanotransduction. Nature 2011; 474(7350): 179-83.
[http://dx.doi.org/10.1038/nature10137] [PMID: 21654799]
[132]
Toyama T, Looney AP, Baker BM, et al. Therapeutic targeting of TAZ and YAP by dimethyl fumarate in systemic sclerosis Fibrosis. J Invest Dermatol 2018; 138(1): 78-88.
[http://dx.doi.org/10.1016/j.jid.2017.08.024] [PMID: 28870693]
[133]
Wang W, Bhattacharyya S, Marangoni RG, et al. The JAK/STAT pathway is activated in systemic sclerosis and is effectively targeted by tofacitinib. J Scleroderma Relat Disord 2020; 5(1): 40-50.
[http://dx.doi.org/10.1177/2397198319865367]
[134]
You H, Xu D, Zhao J, et al. JAK inhibitors: prospects in connective tissue diseases. Clin Rev Allergy Immunol 2020; 59(3): 334-51.
[http://dx.doi.org/10.1007/s12016-020-08786-6] [PMID: 32222877]
[135]
Chakraborty D, Šumová B, Mallano T, et al. Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis. Nat Commun 2017; 8(1): 1130.
[http://dx.doi.org/10.1038/s41467-017-01236-6] [PMID: 29066712]
[136]
Pedroza M, Le TT, Lewis K, et al. STAT-3 contributes to pulmonary fibrosis through epithelial injury and fibroblast-myofibroblast differentiation. FASEB J 2016; 30(1): 129-40.
[http://dx.doi.org/10.1096/fj.15-273953] [PMID: 26324850]
[137]
Dees C, Tomcik M, Palumbo-Zerr K, et al. JAK-2 as a novel mediator of the profibrotic effects of transforming growth factor β in systemic sclerosis. Arthritis Rheum 2012; 64(9): 3006-15.
[http://dx.doi.org/10.1002/art.34500] [PMID: 22549363]
[138]
Papaioannou I, Xu S, Denton CP, Abraham DJ, Ponticos M. STAT3 controls COL1A2 enhancer activation cooperatively with JunB, regulates type I collagen synthesis posttranscriptionally, and is essential for lung myofibroblast differentiation. Mol Biol Cell 2018; 29(2): 84-95.
[http://dx.doi.org/10.1091/mbc.E17-06-0342] [PMID: 29142074]
[139]
Khan K, Xu S, Nihtyanova S, et al. Clinical and pathological significance of interleukin 6 overexpression in systemic sclerosis. Ann Rheum Dis 2012; 71(7): 1235-42.
[http://dx.doi.org/10.1136/annrheumdis-2011-200955] [PMID: 22586157]
[140]
Kawaguchi Y. Contribution of interleukin-6 to the pathogenesis of systemic sclerosis. J Scleroderma Relat Disord 2017; 2(Suppl. 2): S6-S12.
[http://dx.doi.org/10.5301/jsrd.5000258]
[141]
Maurer B, Distler JH, Distler O. The Fra-2 transgenic mouse model of systemic sclerosis. Vascul Pharmacol 2013; 58(3): 194-201.
[http://dx.doi.org/10.1016/j.vph.2012.12.001] [PMID: 23232070]
[142]
Reich N, Maurer B, Akhmetshina A, et al. The transcription factor Fra-2 regulates the production of extracellular matrix in systemic sclerosis. Arthritis Rheum 2010; 62(1): 280-90.
[http://dx.doi.org/10.1002/art.25056] [PMID: 20039427]
[143]
Xu H, Zaidi M, Struve J, et al. Abnormal fibrillin-1 expression and chronic oxidative stress mediate endothelial mesenchymal transition in a murine model of systemic sclerosis. Am J Physiol Cell Physiol 2011; 300: C550-6.
[http://dx.doi.org/10.1152/ajpcell.00123.2010]
[144]
Corallo C, Cutolo M, Kahaleh B, et al. Bosentan and macitentan prevent the endothelial-to-mesenchymal transition (EndoMT) in systemic sclerosis: in vitro study. Arthritis Res Ther 2016; 18(1): 228.
[http://dx.doi.org/10.1186/s13075-016-1122-y] [PMID: 27716320]
[145]
Wermuth PJ, Li Z, Mendoza FA, Jimenez SA. Stimulation of transforming growth factor-β1-induced endothelial-to-mesenchymal transition and tissue fibrosis by endothelin-1 (ET-1): A novel profibrotic effect of ET-1. PLoS One 2016; 11(9): e0161988.
[http://dx.doi.org/10.1371/journal.pone.0161988] [PMID: 27583804]
[146]
Mimura Y, Ihn H, Jinnin M, Asano Y, Yamane K, Tamaki K. Constitutive phosphorylation of focal adhesion kinase is involved in the myofibroblast differentiation of scleroderma fibroblasts. J Invest Dermatol 2005; 124(5): 886-92.
[http://dx.doi.org/10.1111/j.0022-202X.2005.23701.x] [PMID: 15854026]
[147]
Bergmann C, Distler JH. Epigenetic factors as drivers of fibrosis in systemic sclerosis. Epigenomics 2017; 9(4): 463-77.
[http://dx.doi.org/10.2217/epi-2016-0150] [PMID: 28343418]
[148]
Yang J, Tian B, Brasier AR. Targeting chromatin remodeling in inflammation and fibrosis. Adv Protein Chem Struct Biol 2017; 107: 1-36.
[http://dx.doi.org/10.1016/bs.apcsb.2016.11.001] [PMID: 28215221]
[149]
Fioretto BS, Rosa I, Romano E, et al. The contribution of epigenetics to the pathogenesis and gender dimorphism of systemic sclerosis: a comprehensive overview. Ther Adv Musculoskelet Dis 2020.
[150]
Noda S, Asano Y, Nishimura S, et al. Simultaneous downregulation of KLF5 and Fli1 is a key feature underlying systemic sclerosis. Nat Commun 2014; 5: 5797.
[http://dx.doi.org/10.1038/ncomms6797] [PMID: 25504335]
[151]
Altorok N, Tsou PS, Coit P, Khanna D, Sawalha AH. Genome-wide DNA methylation analysis in dermal fibroblasts from patients with diffuse and limited systemic sclerosis reveals common and subset-specific DNA methylation aberrancies. Ann Rheum Dis 2015; 74(8): 1612-20.
[http://dx.doi.org/10.1136/annrheumdis-2014-205303] [PMID: 24812288]
[152]
Zhang Y, Pötter S, Chen CW, et al. Poly(ADP-ribose) polymerase-1 regulates fibroblast activation in systemic sclerosis. Ann Rheum Dis 2018; 77(5): 744-51.
[http://dx.doi.org/10.1136/annrheumdis-2017-212265] [PMID: 29431122]
[153]
Bergmann C, Brandt A, Merlevede B, et al. The histone demethylase Jumonji domain-containing protein 3 (JMJD3) regulates fibroblast activation in systemic sclerosis. Ann Rheum Dis 2018; 77(1): 150-8.
[http://dx.doi.org/10.1136/annrheumdis-2017-211501] [PMID: 29070530]
[154]
Huber LC, Distler JH, Moritz F, et al. Trichostatin A prevents the accumulation of extracellular matrix in a mouse model of bleomycin-induced skin fibrosis. Arthritis Rheum 2007; 56(8): 2755-64.
[http://dx.doi.org/10.1002/art.22759] [PMID: 17665426]
[155]
Chu H, Jiang S, Liu Q, et al. Sirtuin 1 protects against systemic sclerosis-related pulmonary fibrosis by decreasing proinflammatory and profibrotic processes. Am J Respir Cell Mol Biol 2018; 58: 28-39.
[156]
Wyman AE, Noor Z, Fishelevich R, et al. Sirtuin 7 is decreased in pulmonary fibrosis and regulates the fibrotic phenotype of lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 2017; 312(6): L945-58.
[http://dx.doi.org/10.1152/ajplung.00473.2016] [PMID: 28385812]
[157]
Sosulski ML, Gongora R, Feghali-Bostwick C, Lasky JA, Sanchez CG. Sirtuin 3 deregulation promotes pulmonary fibrosis. J Gerontol A Biol Sci Med Sci 2017; 72: 595-602.
[158]
Wei J, Ghosh AK, Chu H, et al. The histone deacetylase sirtuin 1 is reduced in systemic sclerosis and abrogates fibrotic responses by targeting transforming growth factor β signaling. Arthritis Rheumatol 2015; 67(5): 1323-34.
[http://dx.doi.org/10.1002/art.39061] [PMID: 25707573]
[159]
Akamata K, Wei J, Bhattacharyya M, et al. SIRT3 is attenuated in systemic sclerosis skin and lungs, and its pharmacologic activation mitigates organ fibrosis. Oncotarget 2016; 7(43): 69321-36.
[http://dx.doi.org/10.18632/oncotarget.12504] [PMID: 27732568]
[160]
Ghosh AK, Bhattacharyya S, Lafyatis R, et al. p300 is elevated in systemic sclerosis and its expression is positively regulated by TGF-β: epigenetic feed-forward amplification of fibrosis. J Invest Dermatol 2013; 133(5): 1302-10.
[http://dx.doi.org/10.1038/jid.2012.479] [PMID: 23303459]
[161]
Shin JY, Beckett JD, Bagirzadeh R, et al. Epigenetic activation and memory at a TGFB2 enhancer in systemic sclerosis. Sci Transl Med 2019; 11(497): eaaw0790.
[http://dx.doi.org/10.1126/scitranslmed.aaw0790] [PMID: 31217334]
[162]
He Y, Tsou PS, Khanna D, Sawalha AH. Methyl-CpG-binding protein 2 mediates antifibrotic effects in scleroderma fibroblasts. Ann Rheum Dis 2018; 77(8): 1208-18.
[http://dx.doi.org/10.1136/annrheumdis-2018-213022] [PMID: 29760157]
[163]
Santos A, Lagares D. Matrix stiffness: the conductor of organ fibrosis. Curr Rheumatol Rep 2018; 20(1): 2.
[http://dx.doi.org/10.1007/s11926-018-0710-z] [PMID: 29349703]
[164]
Liu F, Mih JD, Shea BS, et al. Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression. J Cell Biol 2010; 190(4): 693-706.
[http://dx.doi.org/10.1083/jcb.201004082] [PMID: 20733059]
[165]
Cutolo M, Ruaro B, Montagna P, et al. Effects of selexipag and its active metabolite in contrasting the profibrotic myofibroblast activity in cultured scleroderma skin fibroblasts. Arthritis Res Ther 2018; 20(1): 77.
[http://dx.doi.org/10.1186/s13075-018-1577-0] [PMID: 29720235]
[166]
Cao L, Lafyatis R, Burkly LC. Increased dermal collagen bundle alignment in systemic sclerosis is associated with a cell migration signature and role of Arhgdib in directed fibroblast migration on aligned ECMs. PLoS One 2017; 12(6): e0180751.
[http://dx.doi.org/10.1371/journal.pone.0180751] [PMID: 28662216]
[167]
Doridot L, Jeljeli M, Chêne C, Batteux F. Implication of oxidative stress in the pathogenesis of systemic sclerosis via inflammation, autoimmunity and fibrosis. Redox Biol 2019; 25: 101122.
[http://dx.doi.org/10.1016/j.redox.2019.101122] [PMID: 30737171]
[168]
Grygiel-Górniak B, Puszczewicz M. Oxidative damage and antioxidative therapy in systemic sclerosis. Mediators Inflamm 2014; 2014: 389582.
[http://dx.doi.org/10.1155/2014/389582] [PMID: 25313270]
[169]
Tsou PS, Talia NN, Pinney AJ, et al. Effect of oxidative stress on protein tyrosine phosphatase 1B in scleroderma dermal fibroblasts. Arthritis Rheum 2012; 64(6): 1978-89.
[http://dx.doi.org/10.1002/art.34336] [PMID: 22161819]
[170]
Bourji K, Meyer A, Chatelus E, et al. High reactive oxygen species in fibrotic and nonfibrotic skin of patients with diffuse cutaneous systemic sclerosis. Free Radic Biol Med 2015; 87: 282-9.
[http://dx.doi.org/10.1016/j.freeradbiomed.2015.07.002] [PMID: 26143738]
[171]
Spadoni T, Svegliati Baroni S, Amico D, et al. A reactive oxygen species-mediated loop maintains increased expression of NADPH oxidases 2 and 4 in skin fibroblasts from patients with systemic sclerosis. Arthritis Rheumatol 2015; 67(6): 1611-22.
[http://dx.doi.org/10.1002/art.39084] [PMID: 25707572]
[172]
Sambo P, Baroni SS, Luchetti M, et al. Oxidative stress in scleroderma: maintenance of scleroderma fibroblast phenotype by the constitutive up-regulation of reactive oxygen species generation through the NADPH oxidase complex pathway. Arthritis Rheum 2001; 44(11): 2653-64.
[http://dx.doi.org/10.1002/1529-0131(200111)44:11<2653:AID-ART445>3.0.CO;2-1] [PMID: 11710721]
[173]
Svegliati S, Cancello R, Sambo P, et al. Platelet-derived growth factor and reactive oxygen species (ROS) regulate Ras protein levels in primary human fibroblasts via ERK1/2. Amplification of ROS and Ras in systemic sclerosis fibroblasts. J Biol Chem 2005; 280(43): 36474-82.
[http://dx.doi.org/10.1074/jbc.M502851200] [PMID: 16081426]
[174]
Baroni SS, Santillo M, Bevilacqua F, et al. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med 2006; 354(25): 2667-76.
[http://dx.doi.org/10.1056/NEJMoa052955] [PMID: 16790699]
[175]
Piera-Velazquez S, Makul A, Jiménez SA. Increased expression of NAPDH oxidase 4 in systemic sclerosis dermal fibroblasts: regulation by transforming growth factor β. Arthritis Rheumatol 2015; 67(10): 2749-58.
[http://dx.doi.org/10.1002/art.39242] [PMID: 26096997]
[176]
Svegliati S, Spadoni T, Moroncini G, Gabrielli A. NADPH oxidase, oxidative stress and fibrosis in systemic sclerosis. Free Radic Biol Med 2018; 125: 90-7.
[http://dx.doi.org/10.1016/j.freeradbiomed.2018.04.554] [PMID: 29694853]
[177]
Qi Q, Mao Y, Tian Y, et al. Geniposide inhibited endothelial-mesenchymal transition via the mTOR signaling pathway in a bleomycin-induced scleroderma mouse model. Am J Transl Res 2017; 9(3): 1025-36.
[PMID: 28386330]
[178]
Worrell JC, O’Reilly S. Bi-directional communication: Conversations between fibroblasts and immune cells in systemic sclerosis. J Autoimmun 2020; 113: 102526.
[http://dx.doi.org/10.1016/j.jaut.2020.102526] [PMID: 32713676]
[179]
Chia JJ, Lu TT. Update on macrophages and innate immunity in scleroderma. Curr Opin Rheumatol 2015; 27(6): 530-6.
[http://dx.doi.org/10.1097/BOR.0000000000000218] [PMID: 26352734]
[180]
Bhattacharyya S, Midwood KS, Yin H, Varga J. Toll-like receptor-4 signaling drives persistent fibroblast activation and prevents fibrosis resolution in scleroderma. Adv Wound Care (New Rochelle) 2017; 6(10): 356-69.
[http://dx.doi.org/10.1089/wound.2017.0732] [PMID: 29062592]
[181]
Fullard N, O’Reilly S. Role of innate immune system in systemic sclerosis. Semin Immunopathol 2015; 37(5): 511-7.
[http://dx.doi.org/10.1007/s00281-015-0503-7] [PMID: 26159672]
[182]
Bhattacharyya S, Wang W, Qin W, et al. TLR4-dependent fibroblast activation drives persistent organ fibrosis in skin and lung. JCI Insight 2018; 3(13): e98850.
[http://dx.doi.org/10.1172/jci.insight.98850] [PMID: 29997297]
[183]
Bhattacharyya S, Wang W, Morales-Nebreda L, et al. Tenascin-C drives persistence of organ fibrosis. Nat Commun 2016; 7: 11703.
[http://dx.doi.org/10.1038/ncomms11703] [PMID: 27256716]
[184]
Bhattacharyya S, Tamaki Z, Wang W, et al. FibronectinEDA promotes chronic cutaneous fibrosis through Toll-like receptor signaling. Sci Transl Med 2014; 6(232): 232ra50.
[http://dx.doi.org/10.1126/scitranslmed.3008264] [PMID: 24739758]
[185]
Fang F, Marangoni RG, Zhou X, et al. Toll-like receptor 9 signaling is augmented in systemic sclerosis and elicits transforming growth factor beta-dependent fibroblast activation. Arthritis Rheumatol 2016; 68(8): 1989-2002.
[http://dx.doi.org/10.1002/art.39655] [PMID: 26946325]
[186]
Artlett CM, Sassi-Gaha S, Hope JL, Feghali-Bostwick CA, Katsikis PD. Mir-155 is overexpressed in systemic sclerosis fibroblasts and is required for NLRP3 inflammasome-mediated collagen synthesis during fibrosis. Arthritis Res Ther 2017; 19(1): 144.
[http://dx.doi.org/10.1186/s13075-017-1331-z] [PMID: 28623945]
[187]
Artlett CM, Sassi-Gaha S, Rieger JL, Boesteanu AC, Feghali-Bostwick CA, Katsikis PD. The inflammasome activating caspase 1 mediates fibrosis and myofibroblast differentiation in systemic sclerosis. Arthritis Rheum 2011; 63(11): 3563-74.
[http://dx.doi.org/10.1002/art.30568] [PMID: 21792841]
[188]
Laurent P, Sisirak V, Lazaro E, et al. Innate immunity in systemic sclerosis fibrosis: recent advances. Front Immunol 2018; 9: 1702.
[http://dx.doi.org/10.3389/fimmu.2018.01702] [PMID: 30083163]
[189]
Maier C, Ramming A, Bergmann C, et al. Inhibition of phosphodiesterase 4 (PDE4) reduces dermal fibrosis by interfering with the release of interleukin-6 from M2 macrophages. Ann Rheum Dis 2017; 76(6): 1133-41.
[http://dx.doi.org/10.1136/annrheumdis-2016-210189] [PMID: 28209630]
[190]
Castelino FV, Bain G, Pace VA, et al. An autotaxin/lysophosphatidic acid/interleukin-6 amplification loop drives scleroderma fibrosis. Arthritis Rheumatol 2016; 68(12): 2964-74.
[http://dx.doi.org/10.1002/art.39797] [PMID: 27390295]
[191]
Brkic Z, van Bon L, Cossu M, et al. The interferon type I signature is present in systemic sclerosis before overt fibrosis and might contribute to its pathogenesis through high BAFF gene expression and high collagen synthesis. Ann Rheum Dis 2016; 75(8): 1567-73.
[http://dx.doi.org/10.1136/annrheumdis-2015-207392] [PMID: 26371289]
[192]
Overed-Sayer C, Rapley L, Mustelin T, Clarke DL. Are mast cells instrumental for fibrotic diseases? Front Pharmacol 2014; 4: 174.
[http://dx.doi.org/10.3389/fphar.2013.00174] [PMID: 24478701]
[193]
Dees C, Akhmetshina A, Zerr P, et al. Platelet-derived serotonin links vascular disease and tissue fibrosis. J Exp Med 2011; 208(5): 961-72.
[http://dx.doi.org/10.1084/jem.20101629] [PMID: 21518801]
[194]
Pincha N, Hajam EY, Badarinath K, et al. PAI1 mediates fibroblast-mast cell interactions in skin fibrosis. J Clin Invest 2018; 128(5): 1807-19.
[http://dx.doi.org/10.1172/JCI99088] [PMID: 29584619]
[195]
Tecchio C, Micheletti A, Cassatella MA. Neutrophil-derived cytokines: facts beyond expression. Front Immunol 2014; 5: 508.
[http://dx.doi.org/10.3389/fimmu.2014.00508] [PMID: 25374568]
[196]
Barnes TC, Anderson ME, Edwards SW, Moots RJ. Neutrophil-derived reactive oxygen species in SSc. Rheumatology (Oxford) 2012; 51(7): 1166-9.
[http://dx.doi.org/10.1093/rheumatology/ker520] [PMID: 22351900]
[197]
Richter K, Kietzmann T. Reactive oxygen species and fibrosis: further evidence of a significant liaison. Cell Tissue Res 2016; 365(3): 591-605.
[http://dx.doi.org/10.1007/s00441-016-2445-3] [PMID: 27345301]
[198]
Gregory AD, Kliment CR, Metz HE, et al. Neutrophil elastase promotes myofibroblast differentiation in lung fibrosis. J Leukoc Biol 2015; 98(2): 143-52.
[http://dx.doi.org/10.1189/jlb.3HI1014-493R] [PMID: 25743626]
[199]
Takemasa A, Ishii Y, Fukuda T. A neutrophil elastase inhibitor prevents bleomycin-induced pulmonary fibrosis in mice. Eur Respir J 2012; 40(6): 1475-82.
[http://dx.doi.org/10.1183/09031936.00127011] [PMID: 22441751]
[200]
Wu M, Pedroza M, Lafyatis R, et al. Identification of cadherin 11 as a mediator of dermal fibrosis and possible role in systemic sclerosis. Arthritis Rheumatol 2014; 66(4): 1010-21.
[http://dx.doi.org/10.1002/art.38275] [PMID: 24757152]
[201]
Bhandari R, Ball MS, Martyanov V, et al. Profibrotic activation of human macrophages in systemic sclerosis. Arthritis Rheumatol 2020; 72(7): 1160-9.
[http://dx.doi.org/10.1002/art.41243] [PMID: 32134204]
[202]
Fasbender F, Widera A, Hengstler JG, Watzl C. Natural killer cells and liver fibrosis. Front Immunol 2016; 7: 19.
[http://dx.doi.org/10.3389/fimmu.2016.00019] [PMID: 26858722]
[203]
Horikawa M, Hasegawa M, Komura K, et al. Abnormal natural killer cell function in systemic sclerosis: altered cytokine production and defective killing activity. J Invest Dermatol 2005; 125(4): 731-7.
[http://dx.doi.org/10.1111/j.0022-202X.2005.23767.x] [PMID: 16185273]
[204]
O’Reilly S, Hügle T, van Laar JM. T cells in systemic sclerosis: a reappraisal. Rheumatology (Oxford) 2012; 51(9): 1540-9.
[http://dx.doi.org/10.1093/rheumatology/kes090] [PMID: 22577083]
[205]
Barron L, Wynn TA. Fibrosis is regulated by Th2 and Th17 responses and by dynamic interactions between fibroblasts and macrophages. Am J Physiol Gastrointest Liver Physiol 2011; 300(5): G723-8.
[http://dx.doi.org/10.1152/ajpgi.00414.2010] [PMID: 21292997]
[206]
Kolahian S, Fernandez IE, Eickelberg O, Hartl D. Immune mechanisms in pulmonary fibrosis. Am J Respir Cell Mol Biol 2016; 55(3): 309-22.
[http://dx.doi.org/10.1165/rcmb.2016-0121TR] [PMID: 27149613]
[207]
Lei L, Zhao C, Qin F, He ZY, Wang X, Zhong XN. Th17 cells and IL-17 promote the skin and lung inflammation and fibrosis process in a bleomycin-induced murine model of systemic sclerosis. Clin Exp Rheumatol 2016; 34(5)(Suppl. 100): 14-22.
[PMID: 26750756]
[208]
McGee HM, Schmidt BA, Booth CJ, et al. IL-22 promotes fibroblast-mediated wound repair in the skin. J Invest Dermatol 2013; 133(5): 1321-9.
[http://dx.doi.org/10.1038/jid.2012.463] [PMID: 23223145]
[209]
Brown M, O’Reilly S. The immunopathogenesis of fibrosis in systemic sclerosis. Clin Exp Immunol 2019; 195(3): 310-21.
[PMID: 30430560]
[210]
Bank I. The role of γδ T Cells in fibrotic diseases. Rambam Maimonides Med J 2016; 7(4): e0029.
[http://dx.doi.org/10.5041/RMMJ.10256] [PMID: 27824548]
[211]
François A, Chatelus E, Wachsmann D, et al. B lymphocytes and B-cell activating factor promote collagen and profibrotic markers expression by dermal fibroblasts in systemic sclerosis. Arthritis Res Ther 2013; 15(5): R168.
[http://dx.doi.org/10.1186/ar4352] [PMID: 24289101]
[212]
Ah Kioon MD, Tripodo C, Fernandez D, et al. Plasmacytoid dendritic cells promote systemic sclerosis with a key role for TLR8. Sci Transl Med 2018; 10(423): eaam8458.
[http://dx.doi.org/10.1126/scitranslmed.aam8458] [PMID: 29321259]
[213]
Asano Y, Varga J. Rationally-based therapeutic disease modification in systemic sclerosis: Novel strategies. Semin Cell Dev Biol 2020; 101: 146-60.
[http://dx.doi.org/10.1016/j.semcdb.2019.12.007] [PMID: 31859147]
[214]
Hinchcliff M, O’Reilly S. Current and potential new targets in systemic sclerosis therapy: a new hope. Curr Rheumatol Rep 2020; 22(8): 42.
[http://dx.doi.org/10.1007/s11926-020-00918-3] [PMID: 32562016]
[215]
Rice LM, Padilla CM, McLaughlin SR, et al. Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients. J Clin Invest 2015; 125(7): 2795-807.
[http://dx.doi.org/10.1172/JCI77958] [PMID: 26098215]
[216]
Ursini F, Grembiale RD, D’Antona L, et al. Oral metformin ameliorates bleomycin-induced skin fibrosis. J Invest Dermatol 2016; 136(9): 1892-4.
[http://dx.doi.org/10.1016/j.jid.2016.05.097] [PMID: 27251791]
[217]
Yoshizaki A, Yanaba K, Yoshizaki A, et al. Treatment with rapamycin prevents fibrosis in tight-skin and bleomycin-induced mouse models of systemic sclerosis. Arthritis Rheum 2010; 62(8): 2476-87.
[http://dx.doi.org/10.1002/art.27498] [PMID: 20506342]
[218]
Yoon KH. Proliferation signal inhibitors for the treatment of refractory autoimmune rheumatic diseases: a new therapeutic option. Ann N Y Acad Sci 2009; 1173: 752-6.
[http://dx.doi.org/10.1111/j.1749-6632.2009.04663.x] [PMID: 19758225]
[219]
Su TI, Khanna D, Furst DE, et al. Rapamycin versus methotrexate in early diffuse systemic sclerosis: results from a randomized, single-blind pilot study. Arthritis Rheum 2009; 60(12): 3821-30.
[http://dx.doi.org/10.1002/art.24986] [PMID: 19950289]
[220]
Fried L, Kirsner RS, Bhandarkar S, Arbiser JL. Efficacy of rapamycin in scleroderma: a case study. Lymphat Res Biol 2008; 6(3-4): 217-9.
[http://dx.doi.org/10.1089/lrb.2008.1006] [PMID: 18950288]
[221]
Beyer C, Reichert H, Akan H, et al. Blockade of canonical Wnt signalling ameliorates experimental dermal fibrosis. Ann Rheum Dis 2013; 72(7): 1255-8.
[http://dx.doi.org/10.1136/annrheumdis-2012-202544] [PMID: 23595143]
[222]
Zhang J, Corciulo C, Liu H, Wilder T, Ito M, Cronstein B. Adenosine A 2a receptor blockade diminishes Wnt/b-catenin signaling in a murine model of bleomycin-induced dermal fibrosis. Am J Pathol 2017; 187(9): 1935-44.
[http://dx.doi.org/10.1016/j.ajpath.2017.05.005] [PMID: 28667836]
[223]
Lafyatis R, Mantero JC, Gordon J, et al. Inhibition of β-catenin signaling in the skin rescues cutaneous adipogenesis in systemic sclerosis: a randomized, double-blind, placebo-controlled trial of C-82. J Invest Dermatol 2017; 137(12): 2473-83.
[http://dx.doi.org/10.1016/j.jid.2017.06.032] [PMID: 28807667]
[224]
Didiasova M, Singh R, Wilhelm J, et al. Pirfenidone exerts antifibrotic effects through inhibition of GLI transcription factors. FASEB J 2017; 31(5): 1916-28.
[http://dx.doi.org/10.1096/fj.201600892RR] [PMID: 28148565]
[225]
Xiao H, Zhang GF, Liao XP, et al. Anti-fibrotic effects of pirfenidone by interference with the hedgehog signalling pathway in patients with systemic sclerosis-associated interstitial lung disease. Int J Rheum Dis 2018; 21(2): 477-86.
[http://dx.doi.org/10.1111/1756-185X.13247] [PMID: 29316328]
[226]
Conte E, Gili E, Fagone E, Fruciano M, Iemmolo M, Vancheri C. Effect of pirfenidone on proliferation, TGF-β-induced myofibroblast differentiation and fibrogenic activity of primary human lung fibroblasts. Eur J Pharm Sci 2014; 58: 13-9.
[http://dx.doi.org/10.1016/j.ejps.2014.02.014] [PMID: 24613900]
[227]
Lehtonen ST, Veijola A, Karvonen H, et al. Pirfenidone and nintedanib modulate properties of fibroblasts and myofibroblasts in idiopathic pulmonary fibrosis. Respir Res 2016; 17: 14.
[http://dx.doi.org/10.1186/s12931-016-0328-5] [PMID: 26846335]
[228]
Khanna D, Albera C, Fischer A, et al. An open-label, phase II study of the safety and tolerability of pirfenidone in patients with scleroderma-associated interstitial lung disease: the LOTUSS trial. J Rheumatol 2016; 43(9): 1672-9.
[http://dx.doi.org/10.3899/jrheum.151322] [PMID: 27370878]
[229]
Distler A, Lang V, Del Vecchio T, et al. Combined inhibition of morphogen pathways demonstrates additive antifibrotic effects and improved tolerability. Ann Rheum Dis 2014; 73(6): 1264-8.
[http://dx.doi.org/10.1136/annrheumdis-2013-204221] [PMID: 24445254]
[230]
Haak AJ, Kostallari E, Sicard D, et al. Selective YAP/TAZ inhibition in fibroblasts via dopamine receptor D1 agonism reverses fibrosis. Sci Transl Med 2019; 11(516): eaau6296.
[http://dx.doi.org/10.1126/scitranslmed.aau6296] [PMID: 31666402]
[231]
O’Reilly S, Ciechomska M, Cant R, van Laar JM. Interleukin-6 (IL-6) trans signaling drives a STAT3-dependent pathway that leads to hyperactive transforming growth factor-β (TGF-β) signaling promoting SMAD3 activation and fibrosis via Gremlin protein. J Biol Chem 2014; 289(14): 9952-60.
[http://dx.doi.org/10.1074/jbc.M113.545822] [PMID: 24550394]
[232]
Piera-Velazquez S, Jimenez SA. Simultaneous inhibition of c-Abl and Src kinases abrogates the exaggerated expression of profibrotic genes in cultured systemic sclerosis dermal fibroblasts. Clin Exp Rheumatol 2018; 36(4)(Suppl. 113): 36-44.
[PMID: 30277861]
[233]
Wermuth PJ, Jimenez SA. Abrogation of transforming growth factor-β-induced tissue fibrosis in TBRIcaCol1a2Cre transgenic mice by the second generation tyrosine kinase inhibitor SKI-606 (Bosutinib). PLoS One 2018; 13(5): e0196559.
[http://dx.doi.org/10.1371/journal.pone.0196559] [PMID: 29718973]
[234]
Huang J, Beyer C, Palumbo-Zerr K, et al. Nintedanib inhibits fibroblast activation and ameliorates fibrosis in preclinical models of systemic sclerosis. Ann Rheum Dis 2016; 75(5): 883-90.
[http://dx.doi.org/10.1136/annrheumdis-2014-207109] [PMID: 25858641]
[235]
Mura M. Use of nintedanib in interstitial lung disease other than idiopathic pulmonary fibrosis: much caution is warranted. Pulm Pharmacol Ther 2021; 66: 101987.
[http://dx.doi.org/10.1016/j.pupt.2020.101987] [PMID: 33387612]
[236]
Makino K, Makino T, Stawski L, Lipson KE, Leask A, Trojanowska M. Anti-connective tissue growth factor (CTGF/CCN2) monoclonal antibody attenuates skin fibrosis in mice models of systemic sclerosis. Arthritis Res Ther 2017; 19(1): 134.
[http://dx.doi.org/10.1186/s13075-017-1356-3] [PMID: 28610597]
[237]
Desallais L, Avouac J, Fréchet M, et al. Targeting IL-6 by both passive or active immunization strategies prevents bleomycin-induced skin fibrosis. Arthritis Res Ther 2014; 16(4): R157.
[http://dx.doi.org/10.1186/ar4672] [PMID: 25059342]
[238]
Kitaba S, Murota H, Terao M, et al. Blockade of interleukin-6 receptor alleviates disease in mouse model of scleroderma. Am J Pathol 2012; 180(1): 165-76.
[http://dx.doi.org/10.1016/j.ajpath.2011.09.013] [PMID: 22062222]
[239]
Denton CP, Ong VH, Xu S, et al. Therapeutic interleukin-6 blockade reverses transforming growth factor-beta pathway activation in dermal fibroblasts: insights from the faSScinate clinical trial in systemic sclerosis. Ann Rheum Dis 2018; 77(9): 1362-71.
[http://dx.doi.org/10.1136/annrheumdis-2018-213031] [PMID: 29853453]
[240]
Khanna D, Denton CP, Jahreis A, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet 2016; 387(10038): 2630-40.
[http://dx.doi.org/10.1016/S0140-6736(16)00232-4] [PMID: 27156934]
[241]
Khanna D, Denton CP, Lin CJF, et al. Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate). Ann Rheum Dis 2018; 77(2): 212-20.
[http://dx.doi.org/10.1136/annrheumdis-2017-211682] [PMID: 29066464]
[242]
Khanna D, Lin CJF, Furst DE, et al. Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med 2020; 8(10): 963-74.
[http://dx.doi.org/10.1016/S2213-2600(20)30318-0] [PMID: 32866440]
[243]
Avouac J, Konstantinova I, Guignabert C, et al. Pan-PPAR agonist IVA337 is effective in experimental lung fibrosis and pulmonary hypertension. Ann Rheum Dis 2017; 76(11): 1931-40.
[http://dx.doi.org/10.1136/annrheumdis-2016-210821] [PMID: 28801346]
[244]
Cipriani P, Di Benedetto P, Ruscitti P, et al. The endothelial-mesenchymal transition in systemic sclerosis is induced by endothelin-1 and transforming growth factor-β and may be blocked by mac-itentan, a dual endothelin-1 receptor antagonist. J Rheumatol 2015; 42(10): 1808-16.
[http://dx.doi.org/10.3899/jrheum.150088] [PMID: 26276964]
[245]
Mor A, Segal Salto M, Katav A, et al. Blockade of CCL24 with a monoclonal antibody ameliorates experimental dermal and pulmonary fibrosis. Ann Rheum Dis 2019; 78(9): 1260-8.
[http://dx.doi.org/10.1136/annrheumdis-2019-215119] [PMID: 31129606]
[246]
Haak AJ, Tsou PS, Amin MA, et al. Targeting the myofibroblast genetic switch: inhibitors of myocardin-related transcription factor/serum response factor-regulated gene transcription prevent fibrosis in a murine model of skin injury. J Pharmacol Exp Ther 2014; 349(3): 480-6.
[http://dx.doi.org/10.1124/jpet.114.213520] [PMID: 24706986]
[247]
Kahl DJ, Hutchings KM, Lisabeth EM, et al. 5-aryl-1,3,4-oxadiazol-2-ylthioalkanoic acids: a highly potent new class of inhibitors of Rho/Myocardin-Related Transcription Factor (MRTF)/Serum Response Factor (SRF)-Mediated Gene Transcription as potential antifibrotic agents for scleroderma. J Med Chem 2019; 62(9): 4350-69.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01772] [PMID: 30951312]
[248]
Hutchings KM, Lisabeth EM, Rajeswaran W, et al. Pharmacokinetic optimitzation of CCG-203971: Novel inhibitors of the Rho/MRTF/SRF transcriptional pathway as potential antifibrotic therapeutics for systemic scleroderma. Bioorg Med Chem Lett 2017; 27(8): 1744-9.
[http://dx.doi.org/10.1016/j.bmcl.2017.02.070] [PMID: 28285914]
[249]
Garcia-Gonzalez E, Selvi E, Balistreri E, et al. Cannabinoids inhibit fibrogenesis in diffuse systemic sclerosis fibroblasts. Rheumatology (Oxford) 2009; 48(9): 1050-6.
[http://dx.doi.org/10.1093/rheumatology/kep189] [PMID: 19589890]
[250]
Balistreri E, Garcia-Gonzalez E, Selvi E, et al. The cannabinoid WIN55, 212-2 abrogates dermal fibrosis in scleroderma bleomycin model. Ann Rheum Dis 2011; 70(4): 695-9.
[http://dx.doi.org/10.1136/ard.2010.137539] [PMID: 21177293]
[251]
Fu Q, Zheng Y, Dong X, Wang L, Jiang CG. Activation of cannabinoid receptor type 2 by JWH133 alleviates bleomycin-induced pulmonary fibrosis in mice. Oncotarget 2017; 8(61): 103486-98.
[http://dx.doi.org/10.18632/oncotarget.21975] [PMID: 29262578]
[252]
Tsou PS, Campbell P, Amin MA, et al. Inhibition of EZH2 prevents fibrosis and restores normal angiogenesis in scleroderma. Proc Natl Acad Sci USA 2019; 116(9): 3695-702.
[http://dx.doi.org/10.1073/pnas.1813006116] [PMID: 30755532]
[253]
Xiao X, Senavirathna LK, Gou X, Huang C, Liang Y, Liu L. EZH2 enhances the differentiation of fibroblasts into myofibroblasts in idiopathic pulmonary fibrosis. Physiol Rep 2016; 4(17): e12915.
[http://dx.doi.org/10.14814/phy2.12915] [PMID: 27582065]
[254]
Kim DJ, Dunleavey JM, Xiao L, et al. Suppression of TGFβ-mediated conversion of endothelial cells and fibroblasts into cancer associated (myo)fibroblasts via HDAC inhibition. Br J Cancer 2018; 118(10): 1359-68.
[http://dx.doi.org/10.1038/s41416-018-0072-3] [PMID: 29695769]
[255]
Bhattacharyya S, Wang W, Graham LVD, Varga J. A20 suppresses canonical Smad-dependent fibroblast activation: novel function for an endogenous inflammatory modulator. Arthritis Res Ther 2016; 18(1): 216.
[http://dx.doi.org/10.1186/s13075-016-1118-7] [PMID: 27716397]
[256]
Ponsoye M, Frantz C, Ruzehaji N, et al. Treatment with abatacept prevents experimental dermal fibrosis and induces regression of established inflammation-driven fibrosis. Ann Rheum Dis 2016; 75(12): 2142-9.
[http://dx.doi.org/10.1136/annrheumdis-2015-208213] [PMID: 26912566]
[257]
Chakravarty EF, Martyanov V, Fiorentino D, et al. Gene expression changes reflect clinical response in a placebo-controlled randomized trial of abatacept in patients with diffuse cutaneous systemic sclerosis. Arthritis Res Ther 2015; 17(1): 159.
[http://dx.doi.org/10.1186/s13075-015-0669-3] [PMID: 26071192]
[258]
Elhai M, Meunier M, Matucci-Cerinic M, et al. Outcomes of patients with systemic sclerosis-associated polyarthritis and myopathy treated with tocilizumab or abatacept: a EUSTAR observational study. Ann Rheum Dis 2013; 72(7): 1217-20.
[http://dx.doi.org/10.1136/annrheumdis-2012-202657] [PMID: 23253926]
[259]
Khanna D, Spino C, Johnson S, et al. Abatacept in early diffuse cutaneous systemic sclerosis: results of a phase II investigator-initiated, multicenter, double-blind, randomized, placebo-controlled trial. Arthritis Rheumatol 2020; 72(1): 125-36.
[http://dx.doi.org/10.1002/art.41055] [PMID: 31342624]
[260]
Matsushita T, Fujimoto M, Hasegawa M, et al. Elevated serum APRIL levels in patients with systemic sclerosis: distinct profiles of systemic sclerosis categorized by APRIL and BAFF. J Rheumatol 2007; 34(10): 2056-62.
[PMID: 17896803]
[261]
Matsushita T, Kobayashi T, Mizumaki K, et al. BAFF inhibition attenuates fibrosis in scleroderma by modulating the regulatory and effector B cell balance. Sci Adv 2018; 4(7): eaas9944.
[http://dx.doi.org/10.1126/sciadv.aas9944] [PMID: 30009261]
[262]
Gordon JK, Martyanov V, Franks JM, et al. Belimumab for the treatment of early diffuse systemic sclerosis: results of a randomized, double-blind, placebo-controlled, pilot trial. Arthritis Rheumatol 2018; 70(2): 308-16.
[http://dx.doi.org/10.1002/art.40358] [PMID: 29073351]
[263]
Lafyatis R, Kissin E, York M, et al. B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum 2009; 60(2): 578-83.
[http://dx.doi.org/10.1002/art.24249] [PMID: 19180481]
[264]
Smith V, Van Praet JT, Vandooren B, et al. Rituximab in diffuse cutaneous systemic sclerosis: an open-label clinical and histopathological study. Ann Rheum Dis 2010; 69(1): 193-7.
[http://dx.doi.org/10.1136/ard.2008.095463] [PMID: 19103636]
[265]
Daoussis D, Liossis SN, Tsamandas AC, et al. Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology (Oxford) 2010; 49(2): 271-80.
[http://dx.doi.org/10.1093/rheumatology/kep093] [PMID: 19447770]
[266]
Jordan S, Distler JH, Maurer B, et al. Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Ann Rheum Dis 2015; 74(6): 1188-94.
[http://dx.doi.org/10.1136/annrheumdis-2013-204522] [PMID: 24442885]
[267]
Daoussis D, Melissaropoulos K, Sakellaropoulos G, et al. A multicenter, open-label, comparative study of B-cell depletion therapy with Rituximab for systemic sclerosis-associated interstitial lung disease. Semin Arthritis Rheum 2017; 46(5): 625-31.
[http://dx.doi.org/10.1016/j.semarthrit.2016.10.003] [PMID: 27839742]
[268]
Bosello SL, De Luca G, Rucco M, et al. Long-term efficacy of B cell depletion therapy on lung and skin involvement in diffuse systemic sclerosis. Semin Arthritis Rheum 2015; 44(4): 428-36.
[http://dx.doi.org/10.1016/j.semarthrit.2014.09.002] [PMID: 25300701]
[269]
Ebata S, Yoshizaki A, Fukasawa T, et al. Rituximab therapy is more effective than cyclophosphamide therapy for Japanese patients with anti-topoisomerase I-positive systemic sclerosis-associated interstitial lung disease. J Dermatol 2019; 46(11): 1006-13.
[http://dx.doi.org/10.1111/1346-8138.15079] [PMID: 31502326]
[270]
Streicher K, Sridhar S, Kuziora M, et al. Baseline plasma cell gene signature predicts improvement in systemic sclerosis skin scores following treatment with inebilizumab (MEDI-551) and correlates with disease activity in systemic lupus erythematosus and chronic obstructive pulmonary disease. Arthritis Rheumatol 2018; 70(12): 2087-95.
[http://dx.doi.org/10.1002/art.40656] [PMID: 29956883]
[271]
Becker MO, Brückner C, Scherer HU, et al. The monoclonal anti-CD25 antibody basiliximab for the treatment of progressive systemic sclerosis: an open-label study. Ann Rheum Dis 2011; 70(7): 1340-1.
[http://dx.doi.org/10.1136/ard.2010.137935] [PMID: 21068100]

Rights & Permissions Print Cite
Article Metrics
35
1
© 2024 Bentham Science Publishers | Privacy Policy