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Fibrosis pp 1-23 | Cite as

Human Fibrotic Diseases: Current Challenges in Fibrosis Research

  • Joel Rosenbloom
  • Edward Macarak
  • Sonsoles Piera-Velazquez
  • Sergio A. Jimenez
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1627)

Abstract

Human fibrotic diseases constitute a major health problem worldwide owing to the large number of affected individuals, the incomplete knowledge of the fibrotic process pathogenesis, the marked heterogeneity in their etiology and clinical manifestations, the absence of appropriate and fully validated biomarkers, and, most importantly, the current void of effective disease-modifying therapeutic agents. The fibrotic disorders encompass a wide spectrum of clinical entities including systemic fibrotic diseases such as systemic sclerosis (SSc), sclerodermatous graft vs. host disease, and nephrogenic systemic fibrosis, as well as numerous organ-specific disorders including radiation-induced fibrosis and cardiac, pulmonary, liver, and kidney fibrosis. Although their causative mechanisms are quite diverse and in several instances have remained elusive, these diseases share the common feature of an uncontrolled and progressive accumulation of fibrotic tissue in affected organs causing their dysfunction and ultimate failure. Despite the remarkable heterogeneity in the etiologic mechanisms responsible for the development of fibrotic diseases and in their clinical manifestations, numerous studies have identified activated myofibroblasts as the common cellular element ultimately responsible for the replacement of normal tissues with nonfunctional fibrotic tissue. Critical signaling cascades, initiated primarily by transforming growth factor-β (TGF-β), but also involving numerous cytokines and signaling molecules which stimulate profibrotic reactions in myofibroblasts, offer potential therapeutic targets. Here, we briefly review the current knowledge of the molecular mechanisms involved in the development of tissue fibrosis and point out some of the most important challenges to research in the fibrotic diseases and to the development of effective therapeutic approaches for this often fatal group of disorders. Efforts to further clarify the complex pathogenetic mechanisms of the fibrotic process should be encouraged to attain the elusive goal of developing effective therapies for these serious, untreatable, and often fatal disorders.

Key words

Fibrotic disease Fibrosis Transforming growth factor-β (TGF-β) Myofibroblasts Extracellular matrix Collagen Systemic sclerosis Idiopathic pulmonary fibrosis 

Notes

Acknowledgments

Partially supported by NIH grant AR 19616 to SAJ. We thank the expert assistance of Alana Pagano and Carol Kelly in the preparation of the manuscript.

References

  1. 1.
    Wynn TA (2008) Cellular and molecular mechanisms of fibrosis. J Pathol 214(2):199–210. doi: 10.1002/path.2277 PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Rosenbloom J, Castro SV, Jimenez SA (2010) Narrative review: fibrotic diseases: cellular and molecular mechanisms and novel therapies. Ann Intern Med 152(3):159–166. doi: 10.7326/0003-4819-152-3-201002020-00007 PubMedCrossRefGoogle Scholar
  3. 3.
    Rockey DC, Bell PD, Hill JA (2015) Fibrosis – a common pathway to organ injury and failure. N Engl J Med 373(1):96. doi: 10.1056/NEJMc1504848
  4. 4.
    Varga J, Abraham D (2007) Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest 117(3):557–567. doi: 10.1172/jci31139 PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Gabrielli A, Avvedimento EV, Krieg T (2009) Scleroderma. N Engl J Med 360(19):1989–2003. doi: 10.1056/NEJMra0806188 PubMedCrossRefGoogle Scholar
  6. 6.
    Ho YY, Lagares D, Tager AM et al (2014) Fibrosis – a lethal component of systemic sclerosis. Nat Rev Rheumatol 10(7):390–402. doi: 10.1038/nrrheum.2014.53
  7. 7.
    Cowper SE, Su LD, Bhawan J et al (2001) Nephrogenic fibrosing dermopathy. Am J Dermatopathol 23(5):383–393. doi: 10.1111/j.0303-6987.2005.0320e.x PubMedCrossRefGoogle Scholar
  8. 8.
    Mendoza FA, Artlett CM, Sandorfi N et al (2006) Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature. Semin Arthritis Rheum 35(4):238–249. doi: 10.1016/j.semarthrit.2005.08.002 PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Piera-Velazquez S, Mendoza FA, Jimenez SA (2016) Endothelial to mesenchymal transition (EndoMT) in the pathogenesis of human fibrotic diseases. J Clin Med 5(4). doi: 10.3390/jcm5040045
  10. 10.
    Jimenez SA, Hitraya E, Varga J (1996) Pathogenesis of scleroderma. Collagen. Rheum Dis Clin N Am 22(4):647–674CrossRefGoogle Scholar
  11. 11.
    Rosenbloom J, Mendoza FA, Jimenez SA (2013) Strategies for anti-fibrotic therapies. Biochim Biophys Acta 1832(7):1088–1103. doi: 10.1016/j.bbadis.2012.12.007 PubMedCrossRefGoogle Scholar
  12. 12.
    Castelino FV, Varga J (2014) Emerging cellular and molecular targets in fibrosis: implications for scleroderma pathogenesis and targeted therapy. Curr Opin Rheumatol 26(6):607–614. doi: 10.1097/bor.0000000000000110 PubMedCrossRefGoogle Scholar
  13. 13.
    Thannickal VJ, Henke CA, Horowitz JC et al (2014) Matrix biology of idiopathic pulmonary fibrosis: a workshop report of the National Heart, Lung, and Blood Institute. Am J Pathol 184(6):1643–1651. doi: 10.1016/j.ajpath.2014.02.003 PubMedCrossRefGoogle Scholar
  14. 14.
    Karsdal MA, Manon-Jensen T, Genovese F et al (2015) Novel insights into the function and dynamics of extracellular matrix in liver fibrosis. Am J Physiol Gastrointest Liver Physiol 308(10):G807–G830. doi: 10.1152/ajpgi.00447.2014 PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Denton CP (2015) Systemic sclerosis: from pathogenesis to targeted therapy. Clin Exp Rheumatol 33(4 Suppl 92):S3–S7PubMedGoogle Scholar
  16. 16.
    Gabbiani G (1981) The myofibroblast: a key cell for wound healing and fibrocontractive diseases. Prog Clin Biol Res 54:183–194PubMedGoogle Scholar
  17. 17.
    Desmouliere A (1995) Factors influencing myofibroblast differentiation during wound healing and fibrosis. Cell Biol Int 19(5):471–476. doi: 10.1006/cbir.1995.1090 PubMedCrossRefGoogle Scholar
  18. 18.
    McAnulty RJ (2007) Fibroblasts and myofibroblasts: their source, function and role in disease. Int J Biochem Cell Biol 39(4):666–671. doi: 10.1016/j.biocel.2006.11.005 PubMedCrossRefGoogle Scholar
  19. 19.
    Hinz B, Phan SH, Thannickal VJ et al (2007) The myofibroblast: one function, multiple origins. Am J Pathol 170(6):1807–1816. doi: 10.2353/ajpath.2007.070112 PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Hinz B, Phan SH, Thannickal VJ et al (2012) Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol 180(4):1340–1355. doi: 10.1016/j.ajpath.2012.02.004 PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Hu B, Phan SH (2013) Myofibroblasts. Curr Opin Rheumatol 25(1):71–77. doi: 10.1097/BOR.0b013e32835b1352 PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Kirk TZ, Mark ME, Chua CC et al (1995) Myofibroblasts from scleroderma skin synthesize elevated levels of collagen and tissue inhibitor of metalloproteinase (TIMP-1) with two forms of TIMP-1. J Biol Chem 270(7):3423–3428PubMedCrossRefGoogle Scholar
  23. 23.
    Abraham DJ, Eckes B, Rajkumar V et al (2007) New developments in fibroblast and myofibroblast biology: implications for fibrosis and scleroderma. Curr Rheumatol Rep 9(2):136–143. doi: 10.1007/s11926-007-0008-z PubMedCrossRefGoogle Scholar
  24. 24.
    Gilbane AJ, Denton CP, Holmes AM (2013) Scleroderma pathogenesis: a pivotal role for fibroblasts as effector cells. Arthritis Res Ther 15(3):215. doi: 10.1186/ar4230 PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Kendall RT, Feghali-Bostwick CA (2014) Fibroblasts in fibrosis: novel roles and mediators. Front Pharmacol 5:123. doi: 10.3389/fphar.2014.00123 PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Laurent GJ, Chambers RC, Hill MR et al (2007) Regulation of matrix turnover: fibroblasts, forces, factors and fibrosis. Biochem Soc Trans 35(Pt 4):647–651. doi: 10.1042/bst0350647 PubMedCrossRefGoogle Scholar
  27. 27.
    Wells RG, Discher DE (2008) Matrix elasticity, cytoskeletal tension, and TGF-beta: the insoluble and soluble meet. Sci Signal 1(10):pe13. doi: 10.1126/stke.110pe13 PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Hinz B (2009) Tissue stiffness, latent TGF-beta1 activation, and mechanical signal transduction: implications for the pathogenesis and treatment of fibrosis. Curr Rheumatol Rep 11(2):120–126PubMedCrossRefGoogle Scholar
  29. 29.
    Parker MW, Rossi D, Peterson M et al (2014) Fibrotic extracellular matrix activates a profibrotic positive feedback loop. J Clin Invest 124(4):1622–1635. doi: 10.1172/jci71386 PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Rittié L (2015) Another dimension to the importance of the extracellular matrix in fibrosis. J Cell Commun Signal 9(1):99–100. doi: 10.1007/s12079-015-0282-x PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Postlethwaite AE, Shigemitsu H, Kanangat S (2004) Cellular origins of fibroblasts: possible implications for organ fibrosis in systemic sclerosis. Curr Opin Rheumatol 16(6):733–738PubMedCrossRefGoogle Scholar
  32. 32.
    Humphreys BD, Lin SL, Kobayashi A et al (2010) Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol 176(1):85–97. doi: 10.2353/ajpath.2010.090517 PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Duffield JS (2014) Cellular and molecular mechanisms in kidney fibrosis. J Clin Invest 124(6):2299–2306. doi: 10.1172/JCI72267 PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Kramann R, Humphreys BD (2014) Kidney pericytes: roles in regeneration and fibrosis. Semin Nephrol 34(4):374–383. doi: 10.1016/j.semnephrol.2014.06.004 PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Kramann R, Schneider RK, DiRocco DP et al (2015) Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis. Cell Stem Cell 16(1):51–66. doi: 10.1016/j.stem.2014.11.004 PubMedCrossRefGoogle Scholar
  36. 36.
    Onuora S (2015) Connective tissue diseases: adipocyte-myofibroblast transition: linking intradermal fat loss to skin fibrosis in SSc. Nat Rev Rheumatol 11(2):63. doi: 10.1038/nrrheum.2014.223 PubMedCrossRefGoogle Scholar
  37. 37.
    Marangoni RG, Korman BD, Wei J et al (2015) Myofibroblasts in murine cutaneous fibrosis originate from adiponectin-positive intradermal progenitors. Arthritis Rheumatol 67(4):1062–1073. doi: 10.1002/art.38990 PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Kruglikov IL, Scherer PE (2016) Dermal adipocytes: from irrelevance to metabolic targets? Trends Endocrinol Metab 27(1):1–10. doi: 10.1016/j.tem.2015.11.002 PubMedCrossRefGoogle Scholar
  39. 39.
    Martins V, Gonzalez De Los Santos F, Wu Z et al (2015) FIZZ1-induced myofibroblast transdifferentiation from adipocytes and its potential role in dermal fibrosis and lipoatrophy. Am J Pathol 185(10):2768–2776. doi: 10.1016/j.ajpath.2015.06.005 PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Resovi A, Pinessi D, Chiorino G et al (2014) Current understanding of the thrombospondin-1 interactome. Matrix Biol 37:83–91. doi: 10.1016/j.matbio.2014.01.012 PubMedCrossRefGoogle Scholar
  41. 41.
    Murphy-Ullrich JE, Sage EH (2014) Revisiting the matricellular concept. Matrix Biol 37:1–14. doi: 10.1016/j.matbio.2014.07.005 PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Iozzo RV, Schaefer L (2015) Proteoglycan form and function: a comprehensive nomenclature of proteoglycans. Matrix Biol 42:11–55. doi: 10.1016/j.matbio.2015.02.003 PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Kramann R, DiRocco DP, Humphreys BD (2013) Understanding the origin, activation and regulation of matrix-producing myofibroblasts for treatment of fibrotic disease. J Pathol 231(3):273–289PubMedCrossRefGoogle Scholar
  44. 44.
    Roberts AB, Sporn MB, Assoian RK et al (1986) Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A 83(12):4167–4171Google Scholar
  45. 45.
    Sporn MB, Roberts AB (1989) Transforming growth factor-beta. Multiple actions and potential clinical applications. JAMA 262(7):938–941PubMedCrossRefGoogle Scholar
  46. 46.
    Santibanez JF, Quintanilla M, Bernabeu C (2011) TGF-beta/TGF-beta receptor system and its role in physiological and pathological conditions. Clin Sci (Lond) 121(6):233–251. doi: 10.1042/cs20110086 CrossRefGoogle Scholar
  47. 47.
    Moses HL, Roberts AB, Derynck R (2016) The discovery and early days of TGF-beta: a historical perspective. Cold Spring Harb Perspect Biol 8(7). doi: 10.1101/cshperspect.a021865
  48. 48.
    Fujio K, Komai T, Inoue M et al (2016) Revisiting the regulatory roles of the TGF-beta family of cytokines. Autoimmun Rev 15(9):917–922. doi: 10.1016/j.autrev.2016.07.007 PubMedCrossRefGoogle Scholar
  49. 49.
    Goumans MJ, Liu Z, ten Dijke P (2009) TGF-beta signaling in vascular biology and dysfunction. Cell Res 19(1):116–127. doi: 10.1038/cr.2008.326 PubMedCrossRefGoogle Scholar
  50. 50.
    Medici D, Potenta S, Kalluri R (2011) Transforming growth factor-beta2 promotes Snail-mediated endothelial-mesenchymal transition through convergence of Smad-dependent and Smad-independent signalling. Biochem J 437(3):515–520. doi: 10.1042/bj20101500 PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    van Meeteren LA, ten Dijke P (2012) Regulation of endothelial cell plasticity by TGF-beta. Cell Tissue Res 347(1):177–186. doi: 10.1007/s00441-011-1222-6 PubMedCrossRefGoogle Scholar
  52. 52.
    Border WA, Noble NA (1994) Transforming growth factor beta in tissue fibrosis. N Engl J Med 331(19):1286–1292. doi: 10.1056/nejm199411103311907 PubMedCrossRefGoogle Scholar
  53. 53.
    Pohlers D, Brenmoehl J, Loffler I et al (2009) TGF-beta and fibrosis in different organs – molecular pathway imprints. Biochim Biophys Acta 1792(8):746–756. doi: 10.1016/j.bbadis.2009.06.004
  54. 54.
    Varga J, Whitfield ML (2009) Transforming growth factor-beta in systemic sclerosis (scleroderma). Front Biosci (Schol Ed) 1:226–235CrossRefGoogle Scholar
  55. 55.
    Jimenez SA, Castro SV, Piera-Velazquez S (2010) Role of growth factors in the pathogenesis of tissue fibrosis in systemic sclerosis. Curr Rheumatol Rev 6(4):283–294PubMedCrossRefGoogle Scholar
  56. 56.
    Biernacka A, Dobaczewski M, Frangogiannis NG (2011) TGF-beta signaling in fibrosis. Growth Factors 29(5):196–202. doi: 10.3109/08977194.2011.595714 PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Lafyatis R (2014) Transforming growth factor beta – at the centre of systemic sclerosis. Nat Rev Rheumatol 10(12):706–719. doi: 10.1038/nrrheum.2014.137
  58. 58.
    Meng XM, Nikolic-Paterson DJ, Lan HY (2016) TGF-beta: the master regulator of fibrosis. Nat Rev Nephrol 12(6):325–338. doi: 10.1038/nrneph.2016.48 PubMedCrossRefGoogle Scholar
  59. 59.
    Miyazono K, Olofsson A, Colosetti P et al (1991) A role of the latent TGF-beta 1-binding protein in the assembly and secretion of TGF-beta 1. EMBO J 10(5):1091–1101PubMedPubMedCentralGoogle Scholar
  60. 60.
    Taipale J, Miyazono K, Heldin CH et al (1994) Latent transforming growth factor-beta 1 associates to fibroblast extracellular matrix via latent TGF-beta binding protein. J Cell Biol 124(1–2):171–181PubMedCrossRefGoogle Scholar
  61. 61.
    Murphy-Ullrich JE, Poczatek M (2000) Activation of latent TGF-beta by thrombospondin-1: mechanisms and physiology. Cytokine Growth Factor Rev 11(1–2):59–69PubMedCrossRefGoogle Scholar
  62. 62.
    Sheppard D (2005) Integrin-mediated activation of latent transforming growth factor beta. Cancer Metastasis Rev 24(3):395–402. doi: 10.1007/s10555-005-5131-6 PubMedCrossRefGoogle Scholar
  63. 63.
    Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425(6958):577–584. doi: 10.1038/nature02006 PubMedCrossRefGoogle Scholar
  64. 64.
    ten Dijke P, Hill CS (2004) New insights into TGF-beta-Smad signalling. Trends Biochem Sci 29(5):265–273. doi: 10.1016/j.tibs.2004.03.008 PubMedCrossRefGoogle Scholar
  65. 65.
    Moustakas A, Heldin CH (2005) Non-Smad TGF-beta signals. J Cell Sci 118(Pt 16):3573–3584. doi: 10.1242/jcs.02554 PubMedCrossRefGoogle Scholar
  66. 66.
    Wilkes MC, Leof EB (2006) Transforming growth factor beta activation of c-Abl is independent of receptor internalization and regulated by phosphatidylinositol 3-kinase and PAK2 in mesenchymal cultures. J Biol Chem 281(38):27846–27854. doi: 10.1074/jbc.M603721200
  67. 67.
    Jimenez SA, Gaidarova S, Saitta B et al (2001) Role of protein kinase C-delta in the regulation of collagen gene expression in scleroderma fibroblasts. J Clin Invest 108(9):1395–1403. doi: 10.1172/jci12347 PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Bujor AM, Asano Y, Haines P et al (2011) The c-Abl tyrosine kinase controls protein kinase C delta-induced Fli-1 phosphorylation in human dermal fibroblasts. Arthritis Rheum 63(6):1729–1737. doi: 10.1002/art.30284 PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Lawler S, Feng XH, Chen RH et al (1997) The type II transforming growth factor-beta receptor autophosphorylates not only on serine and threonine but also on tyrosine residues. J Biol Chem 272(23):14850–14859PubMedCrossRefGoogle Scholar
  70. 70.
    Galliher AJ, Schiemann WP (2007) Src phosphorylates Tyr284 in TGF-beta type II receptor and regulates TGF-beta stimulation of p38 MAPK during breast cancer cell proliferation and invasion. Cancer Res 67(8):3752–3758. doi: 10.1158/0008-5472.can-06-3851
  71. 71.
    Pannu J, Asano Y, Nakerakanti S et al (2008) Smad1 pathway is activated in systemic sclerosis fibroblasts and is targeted by imatinib mesylate. Arthritis Rheum 58(8):2528–2537. doi: 10.1002/art.23698 PubMedCrossRefGoogle Scholar
  72. 72.
    Caraci F, Gili E, Calafiore M et al (2008) TGF-beta1 targets the GSK-3 beta/beta-catenin pathway via ERK activation in the transition of human lung fibroblasts into myofibroblasts. Pharmacol Res 57(4):274–282. doi: 10.1016/j.phrs.2008.02.001 PubMedCrossRefGoogle Scholar
  73. 73.
    Andrianifahanana M, Wilkes MC, Gupta SK et al (2013) Profibrotic TGFbeta responses require the cooperative action of PDGF and ErbB receptor tyrosine kinases. FASEB J 27(11):4444–4454. doi: 10.1096/fj.12-224907 PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Chen D, Zhao M, Mundy GR (2004) Bone morphogenetic proteins. Growth Factors 22(4):233–241. doi: 10.1080/08977190412331279890 PubMedCrossRefGoogle Scholar
  75. 75.
    Mulloy B, Rider CC (2015) The bone morphogenetic proteins and their antagonists. Vitam Horm 99:63–90. doi: 10.1016/bs.vh.2015.06.004 PubMedCrossRefGoogle Scholar
  76. 76.
    Bi J, Ge S (2014) Potential roles of BMP9 in liver fibrosis. Int J Mol Sci 15(11):20656–20667. doi: 10.3390/ijms151120656
  77. 77.
    Li RX, Yiu WH, Tang SC (2015) Role of bone morphogenetic protein-7 in renal fibrosis. Front Physiol 6:114. doi: 10.3389/fphys.2015.00114
  78. 78.
    Zeisberg M, Hanai J, Sugimoto H et al (2003) BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 9(7):964–968. doi: 10.1038/nm888 PubMedCrossRefGoogle Scholar
  79. 79.
    Weiskirchen R, Meurer SK, Gressner OA et al (2009) BMP-7 as antagonist of organ fibrosis. Front Biosci (Landmark Ed) 14:4992–5012CrossRefGoogle Scholar
  80. 80.
    Weiskirchen R, Meurer SK (2013) BMP-7 counteracting TGF-beta1 activities in organ fibrosis. Front Biosci (Landmark Ed) 18:1407–1434CrossRefGoogle Scholar
  81. 81.
    Miyazono K, Kusanagi K, Inoue H (2001) Divergence and convergence of TGF-beta/BMP signaling. J Cell Physiol 187(3):265–276. doi: 10.1002/jcp.1080 PubMedCrossRefGoogle Scholar
  82. 82.
    Miyazawa K, Shinozaki M, Hara T et al (2002) Two major Smad pathways in TGF-beta superfamily signalling. Genes Cells 7(12):1191–1204PubMedCrossRefGoogle Scholar
  83. 83.
    Meng XM, Chung AC, Lan HY (2013) Role of the TGF-beta/BMP-7/Smad pathways in renal diseases. Clin Sci (Lond) 124(4):243–254. doi: 10.1042/CS20120252 CrossRefGoogle Scholar
  84. 84.
    Miyazono K, Kamiya Y, Morikawa M (2010) Bone morphogenetic protein receptors and signal transduction. J Biochem 147(1):35–51. doi: 10.1093/jb/mvp148 PubMedCrossRefGoogle Scholar
  85. 85.
    Mueller TD, Nickel J (2012) Promiscuity and specificity in BMP receptor activation. FEBS Lett 586(14):1846–1859. doi: 10.1016/j.febslet.2012.02.043 PubMedCrossRefGoogle Scholar
  86. 86.
    Bai S, Shi X, Yang X et al (2000) Smad6 as a transcriptional corepressor. J Biol Chem 275(12):8267–8270PubMedCrossRefGoogle Scholar
  87. 87.
    Wang S, Hirschberg R (2004) Bone morphogenetic protein-7 signals opposing transforming growth factor beta in mesangial cells. J Biol Chem 279(22):23200–23206. doi: 10.1074/jbc.M311998200 PubMedCrossRefGoogle Scholar
  88. 88.
    Yan X, Liu Z, Chen Y (2009) Regulation of TGF-beta signaling by Smad7. Acta Biochim Biophys Sin Shanghai 41(4):263–272PubMedCrossRefGoogle Scholar
  89. 89.
    Motazed R, Colville-Nash P, Kwan JT et al (2008) BMP-7 and proximal tubule epithelial cells: activation of multiple signaling pathways reveals a novel anti-fibrotic mechanism. Pharm Res 25(10):2440–2446. doi: 10.1007/s11095-008-9551-1 PubMedCrossRefGoogle Scholar
  90. 90.
    Wang S, Hirschberg R (2003) BMP7 antagonizes TGF-beta-dependent fibrogenesis in mesangial cells. Am J Physiol Renal Physiol 284(5):F1006–F1013. doi: 10.1152/ajprenal.00382.2002 PubMedCrossRefGoogle Scholar
  91. 91.
    Wang SN, Lapage J, Hirschberg R (2001) Loss of tubular bone morphogenetic protein-7 in diabetic nephropathy. J Am Soc Nephrol 12(11):2392–2399Google Scholar
  92. 92.
    Wang S, de Caestecker M, Kopp J et al (2006) Renal bone morphogenetic protein-7 protects against diabetic nephropathy. J Am Soc Nephrol 17(9):2504–2512. doi: 10.1681/ASN.2006030278 PubMedCrossRefGoogle Scholar
  93. 93.
    Munoz-Felix JM, Gonzalez-Nunez M, Martinez-Salgado C et al (2015) TGF-beta/BMP proteins as therapeutic targets in renal fibrosis. Where have we arrived after 25 years of trials and tribulations? Pharmacol Ther 156:44–58. doi: 10.1016/j.pharmthera.2015.10.003 PubMedCrossRefGoogle Scholar
  94. 94.
    Kessler D, Dethlefsen S, Haase I et al (2001) Fibroblasts in mechanically stressed collagen lattices assume a “synthetic” phenotype. J Biol Chem 276(39):36575–36585. doi: 10.1074/jbc.M101602200 PubMedCrossRefGoogle Scholar
  95. 95.
    Huang X, Yang N, Fiore VF et al (2012) Matrix stiffness-induced myofibroblast differentiation is mediated by intrinsic mechanotransduction. Am J Respir Cell Mol Biol 47(3):340–348. doi: 10.1165/rcmb.2012-0050OC PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Hayashida T, Decaestecker M, Schnaper HW (2003) Cross-talk between ERK MAP kinase and Smad signaling pathways enhances TGF-beta-dependent responses in human mesangial cells. FASEB J 17(11):1576–1578. doi: 10.1096/fj.03-0037fje PubMedGoogle Scholar
  97. 97.
    Thorin E, Clozel M (2010) The cardiovascular physiology and pharmacology of endothelin-1. Adv Pharmacol 60:1–26. doi: 10.1016/b978-0-12-385061-4.00001-5 PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Kawanabe Y, Nauli SM (2011) Endothelin. Cell Mol Life Sci 68(2):195–203. doi: 10.1007/s00018-010-0518-0 PubMedCrossRefGoogle Scholar
  99. 99.
    Shi-Wen X, Denton CP, Dashwood MR et al (2001) Fibroblast matrix gene expression and connective tissue remodeling: role of endothelin-1. J Invest Dermatol 116(3):417–425. doi: 10.1046/j.1523-1747.2001.01256.x PubMedCrossRefGoogle Scholar
  100. 100.
    Xu SW, Howat SL, Renzoni EA et al (2004) Endothelin-1 induces expression of matrix-associated genes in lung fibroblasts through MEK/ERK. J Biol Chem 279(22):23098–23103. doi: 10.1074/jbc.M311430200 PubMedCrossRefGoogle Scholar
  101. 101.
    Jing J, Dou TT, Yang JQ et al (2015) Role of endothelin-1 in the skin fibrosis of systemic sclerosis. Eur Cytokine Netw 26(1):10–14. doi: 10.1684/ecn.2015.0360
  102. 102.
    Abraham D, Ponticos M, Nagase H (2005) Connective tissue remodeling: cross-talk between endothelins and matrix metalloproteinases. Curr Vasc Pharmacol 3(4):369–379. doi: 10.2174/157016105774329480 PubMedCrossRefGoogle Scholar
  103. 103.
    Park SH, Saleh D, Giaid A et al (1997) Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist. Am J Respir Crit Care Med 156(2 Pt 1):600–608. doi: 10.1164/ajrccm.156.2.9607123
  104. 104.
    Ross B, D’Orleans-Juste P, Giaid A (2010) Potential role of endothelin-1 in pulmonary fibrosis: from the bench to the clinic. Am J Respir Cell Mol Biol 42(1):16–20. doi: 10.1165/rcmb.2009-0175TR
  105. 105.
    Kim KK, Chapman HA (2007) Endothelin-1 as initiator of epithelial-mesenchymal transition: potential new role for endothelin-1 during pulmonary fibrosis. Am J Respir Cell Mol Biol 37(1):1–2. doi: 10.1165/rcmb.2007-0001ED PubMedCrossRefGoogle Scholar
  106. 106.
    Widyantoro B, Emoto N, Nakayama K et al (2010) Endothelial cell-derived endothelin-1 promotes cardiac fibrosis in diabetic hearts through stimulation of endothelial-to-mesenchymal transition. Circulation 121(22):2407–2418. doi: 10.1161/circulationaha.110.938217 PubMedCrossRefGoogle Scholar
  107. 107.
    Cipriani P, Di Benedetto P, Ruscitti P et al (2015) The endothelial-mesenchymal transition in systemic sclerosis is induced by endothelin-1 and transforming growth factor-beta and may be blocked by macitentan, a dual endothelin-1 receptor antagonist. J Rheumatol 42(10):1808–1816. doi: 10.3899/jrheum.150088 PubMedCrossRefGoogle Scholar
  108. 108.
    Wermuth PJ, Li Z, Jimenez SA (2016) Stimulation of TGF-β1-induced endothelial-to-mesenchymal transition and tissue fibrosis by endothelin-1 (ET-1): a novel profibrotic effect of ET-1. PLoS One 11(9):e0161988. doi: 10.1371/journal.pone.0161988 PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Igarashi A, Nashiro K, Kikuchi K et al (1995) Significant correlation between connective tissue growth factor gene expression and skin sclerosis in tissue sections from patients with systemic sclerosis. J Invest Dermatol 105(2):280–284PubMedCrossRefGoogle Scholar
  110. 110.
    Grotendorst GR (1997) Connective tissue growth factor: a mediator of TGF-beta action on fibroblasts. Cytokine Growth Factor Rev 8(3):171–179PubMedCrossRefGoogle Scholar
  111. 111.
    Sato S, Nagaoka T, Hasegawa M et al (2000) Serum levels of connective tissue growth factor are elevated in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis. J Rheumatol 27(1):149–154PubMedGoogle Scholar
  112. 112.
    Leask A, Abraham DJ (2003) The role of connective tissue growth factor, a multifunctional matricellular protein, in fibroblast biology. Biochem Cell Biol 81(6):355–363. doi: 10.1139/o03-069 PubMedCrossRefGoogle Scholar
  113. 113.
    Shi-Wen X, Leask A, Abraham D (2008) Regulation and function of connective tissue growth factor/CCN2 in tissue repair, scarring and fibrosis. Cytokine Growth Factor Rev 19(2):133–144. doi: 10.1016/j.cytogfr.2008.01.002
  114. 114.
    Ponticos M, Holmes AM, Shi-wen X et al (2009) Pivotal role of connective tissue growth factor in lung fibrosis: MAPK-dependent transcriptional activation of type I collagen. Arthritis Rheum 60(7):2142–2155. doi: 10.1002/art.24620 PubMedCrossRefGoogle Scholar
  115. 115.
    Ruperez M, Rodrigues-Diez R, Blanco-Colio LM et al (2007) HMG-CoA reductase inhibitors decrease angiotensin II-induced vascular fibrosis: role of RhoA/ROCK and MAPK pathways. Hypertension 50(2):377–383. doi: 10.1161/hypertensionaha.107.091264 PubMedCrossRefGoogle Scholar
  116. 116.
    Betsholtz C (2003) Biology of platelet-derived growth factors in development. Birth Defects Res C Embryo Today 69(4):272–285. doi: 10.1002/bdrc.10030 PubMedCrossRefGoogle Scholar
  117. 117.
    Alvarez RH, Kantarjian HM, Cortes JE (2006) Biology of platelet-derived growth factor and its involvement in disease. Mayo Clin Proc 81(9):1241–1257. doi: 10.4065/81.9.1241 PubMedCrossRefGoogle Scholar
  118. 118.
    Farooqi AA, Waseem S, Riaz AM et al (2011) PDGF: the nuts and bolts of signalling toolbox. Tumour Biol 32(6):1057–1070. doi: 10.1007/s13277-011-0212-3 PubMedCrossRefGoogle Scholar
  119. 119.
    Bonner JC (2004) Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev 15(4):255–273. doi: 10.1016/j.cytogfr.2004.03.006 PubMedCrossRefGoogle Scholar
  120. 120.
    Yamakage A, Kikuchi K, Smith EA et al (1992) Selective upregulation of platelet-derived growth factor alpha receptors by transforming growth factor beta in scleroderma fibroblasts. J Exp Med 175(5):1227–1234PubMedCrossRefGoogle Scholar
  121. 121.
    Tallquist M, Kazlauskas A (2004) PDGF signaling in cells and mice. Cytokine Growth Factor Rev 15(4):205–213. doi: 10.1016/j.cytogfr.2004.03.003 PubMedCrossRefGoogle Scholar
  122. 122.
    Olson LE, Soriano P (2009) Increased PDGFR alpha activation disrupts connective tissue development and drives systemic fibrosis. Dev Cell 16(2):303–313. doi: 10.1016/j.devcel.2008.12.003 PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Czochra P, Klopcic B, Meyer E et al (2006) Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic mice. J Hepatol 45(3):419–428. doi: 10.1016/j.jhep.2006.04.010 PubMedCrossRefGoogle Scholar
  124. 124.
    Ogawa S, Ochi T, Shimada H et al (2010) Anti-PDGF-B monoclonal antibody reduces liver fibrosis development. Hepatol Res 40(11):1128–1141. doi: 10.1111/j.1872-034X.2010.00718.x PubMedCrossRefGoogle Scholar
  125. 125.
    Heldin CH, Westermark B (1999) Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79(4):1283–1316Google Scholar
  126. 126.
    Lam AP, Flozak AS, Russell S et al (2011) Nuclear beta-catenin is increased in systemic sclerosis pulmonary fibrosis and promotes lung fibroblast migration and proliferation. Am J Respir Cell Mol Biol 45(5):915–922. doi: 10.1165/rcmb.2010-0113OC PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Beyer C, Schramm A, Akhmetshina A et al (2012) Beta-catenin is a central mediator of pro-fibrotic Wnt signaling in systemic sclerosis. Ann Rheum Dis 71(5):761–767. doi: 10.1136/annrheumdis-2011-200568 PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Niehrs C (2012) The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol 13(12):767–779. doi: 10.1038/nrm3470 PubMedCrossRefGoogle Scholar
  129. 129.
    Clevers H, Nusse R (2012) Wnt/beta-catenin signaling and disease. Cell 149(6):1192–1205. doi: 10.1016/j.cell.2012.05.012 PubMedCrossRefGoogle Scholar
  130. 130.
    Wei J, Fang F, Lam AP et al (2012) Wnt/beta-catenin signaling is hyperactivated in systemic sclerosis and induces Smad-dependent fibrotic responses in mesenchymal cells. Arthritis Rheum 64(8):2734–2745. doi: 10.1002/art.34424 PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Bergmann C, Distler JH (2016) Canonical Wnt signaling in systemic sclerosis. Lab Investig 96(2):151–155. doi: 10.1038/labinvest.2015.154 PubMedCrossRefGoogle Scholar
  132. 132.
    Nusse R (2005) Wnt signaling in disease and in development. Cell Res 15(1):28–32. doi: 10.1038/sj.cr.7290260 PubMedCrossRefGoogle Scholar
  133. 133.
    Huang H, He X (2008) Wnt/beta-catenin signaling: new (and old) players and new insights. Curr Opin Cell Biol 20(2):119–125. doi: 10.1016/j.ceb.2008.01.009 PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Konigshoff M, Balsara N, Pfaff EM et al (2008) Functional Wnt signaling is increased in idiopathic pulmonary fibrosis. PLoS One 3(5):e2142. doi: 10.1371/journal.pone.0002142 PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    He W, Dai C, Li Y et al (2009) Wnt/beta-catenin signaling promotes renal interstitial fibrosis. J Am Soc Nephrol 20(4):765–776. doi: 10.1681/asn.2008060566 PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    He W, Zhang L, Ni A et al (2010) Exogenously administered secreted frizzled related protein 2 (Sfrp2) reduces fibrosis and improves cardiac function in a rat model of myocardial infarction. Proc Natl Acad Sci U S A 107(49):21110–21115. doi: 10.1073/pnas.1004708107 PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Trensz F, Haroun S, Cloutier A et al (2010) A muscle resident cell population promotes fibrosis in hind limb skeletal muscles of mdx mice through the Wnt canonical pathway. Am J Physiol Cell Physiol 299(5):C939–C947. doi: 10.1152/ajpcell.00253.2010 PubMedCrossRefGoogle Scholar
  138. 138.
    Wei J, Melichian D, Komura K et al (2011) Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: a novel mouse model for scleroderma? Arthritis Rheum 63(6):1707–1717. doi: 10.1002/art.30312 PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Bafico A, Liu G, Yaniv A et al (2001) Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/arrow. Nat Cell Biol 3(7):683–686. doi: 10.1038/35083081 PubMedCrossRefGoogle Scholar
  140. 140.
    Pinzone JJ, Hall BM, Thudi NK et al (2009) The role of Dickkopf-1 in bone development, homeostasis, and disease. Blood 113(3):517–525. doi: 10.1182/blood-2008-03-145169
  141. 141.
    Echelard Y, Epstein DJ, St-Jacques B et al (1993) Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75(7):1417–1430. doi: 10.1016/0092-8674(93)90627-3 PubMedCrossRefGoogle Scholar
  142. 142.
    Rohatgi R, Milenkovic L, Corcoran RB et al (2009) Hedgehog signal transduction by Smoothened: pharmacologic evidence for a 2-step activation process. Proc Natl Acad Sci U S A 106(9):3196–3201. doi: 10.1073/pnas.0813373106 PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Rohatgi R, Scott MP (2007) Patching the gaps in hedgehog signalling. Nat Cell Biol 9(9):1005–1009. doi: 10.1038/ncb435 PubMedCrossRefGoogle Scholar
  144. 144.
    Xie J, Murone M, Luoh SM et al (1998) Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391(6662):90–92. doi: 10.1038/34201 PubMedCrossRefGoogle Scholar
  145. 145.
    Dahmane N, Sanchez P, Gitton Y et al (2001) The sonic hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis. Development 128(24):5201–5212PubMedGoogle Scholar
  146. 146.
    Thayer SP, di Magliano MP, Heiser PW et al (2003) Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425(6960):851–856. doi: 10.1038/nature02009 PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Horn A, Palumbo K, Cordazzo C et al (2012) Hedgehog signaling controls fibroblast activation and tissue fibrosis in systemic sclerosis. Arthritis Rheum 64(8):2724–2733. doi: 10.1002/art.34444 PubMedCrossRefGoogle Scholar
  148. 148.
    D’Souza B, Miyamoto A, Weinmaster G (2008) The many facets of Notch ligands. Oncogene 27(38):5148–5167. doi: 10.1038/onc.2008.229 PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Fortini ME (2009) Notch signaling: the core pathway and its posttranslational regulation. Dev Cell 16(5):633–647. doi: 10.1016/j.devcel.2009.03.010 PubMedCrossRefGoogle Scholar
  150. 150.
    Borggrefe T, Liefke R (2012) Fine-tuning of the intracellular canonical Notch signaling pathway. Cell Cycle 11(2):264–276. doi: 10.4161/cc.11.2.18995 PubMedCrossRefGoogle Scholar
  151. 151.
    Dees C, Tomcik M, Zerr P et al (2011) Notch signalling regulates fibroblast activation and collagen release in systemic sclerosis. Ann Rheum Dis 70(7):1304–1310. doi: 10.1136/ard.2010.134742 PubMedCrossRefGoogle Scholar
  152. 152.
    Kavian N, Servettaz A, Weill B et al (2012) New insights into the mechanism of notch signalling in fibrosis. Open Rheumatol J 6:96–102. doi: 10.2174/1874312901206010096 PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Louvi A, Artavanis-Tsakonas S (2012) Notch and disease: a growing field. Semin Cell Dev Biol 23(4):473–480. doi: 10.1016/j.semcdb.2012.02.005 PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Distler A, Lang V, Del Vecchio T et al (2014) Combined inhibition of morphogen pathways demonstrates additive antifibrotic effects and improved tolerability. Ann Rheum Dis 73(6):1264–1268. doi: 10.1136/annrheumdis-2013-204221 PubMedCrossRefGoogle Scholar
  155. 155.
    Beyer C, Schett G, Gay S et al (2009) Hypoxia. Hypoxia in the pathogenesis of systemic sclerosis. Arthritis Res Ther 11(2):220. doi: 10.1186/ar2598 PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Haase VH (2009) Pathophysiological consequences of HIF activation: HIF as a modulator of fibrosis. Ann N Y Acad Sci 1177:57–65. doi: 10.1111/j.1749-6632.2009.05030.x PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Semenza GL (2012) Hypoxia-inducible factors in physiology and medicine. Cell 148(3):399–408. doi: 10.1016/j.cell.2012.01.021 PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Lokmic Z, Musyoka J, Hewitson TD et al (2012) Hypoxia and hypoxia signaling in tissue repair and fibrosis. Int Rev Cell Mol Biol 296:139–185. doi: 10.1016/b978-0-12-394307-1.00003-5 PubMedCrossRefGoogle Scholar
  159. 159.
    Distler JH, Jungel A, Pileckyte M et al (2007) Hypoxia-induced increase in the production of extracellular matrix proteins in systemic sclerosis. Arthritis Rheum 56(12):4203–4215. doi: 10.1002/art.23074 PubMedCrossRefGoogle Scholar
  160. 160.
    Sanchez-Elsner T, Botella LM, Velasco B et al (2001) Synergistic cooperation between hypoxia and transforming growth factor-beta pathways on human vascular endothelial growth factor gene expression. J Biol Chem 276(42):38527–38535. doi: 10.1074/jbc.M104536200 PubMedCrossRefGoogle Scholar
  161. 161.
    Higgins DF, Kimura K, Bernhardt WM et al (2007) Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest 117(12):3810–3820. doi: 10.1172/jci30487
  162. 162.
    Liu RM, Desai LP (2015) Reciprocal regulation of TGF-beta and reactive oxygen species: a perverse cycle for fibrosis. Redox Biol 6:565–577. doi: 10.1016/j.redox.2015.09.009 PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Richter K, Konzack A, Pihlajaniemi T et al (2015) Redox-fibrosis: impact of TGFbeta1 on ROS generators, mediators and functional consequences. Redox Biol 6:344–352. doi: 10.1016/j.redox.2015.08.015 PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Kliment CR, Oury TD (2010) Oxidative stress, extracellular matrix targets, and idiopathic pulmonary fibrosis. Free Radic Biol Med 49(5):707–717. doi: 10.1016/j.freeradbiomed.2010.04.036 PubMedCrossRefGoogle Scholar
  165. 165.
    Siani A, Tirelli N (2014) Myofibroblast differentiation: main features, biomedical relevance, and the role of reactive oxygen species. Antioxid Redox Signal 21(5):768–785. doi: 10.1089/ars.2013.5724 PubMedCrossRefGoogle Scholar
  166. 166.
    Bourji K, Meyer A, Chatelus E et al (2015) High reactive oxygen species in fibrotic and nonfibrotic skin of patients with diffuse cutaneous systemic sclerosis. Free Radic Biol Med 87:282–289. doi: 10.1016/j.freeradbiomed.2015.07.002 PubMedCrossRefGoogle Scholar
  167. 167.
    Cucoranu I, Clempus R, Dikalova A et al (2005) NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. Circ Res 97(9):900–907. doi: 10.1161/01.res.0000187457.24338.3d PubMedCrossRefGoogle Scholar
  168. 168.
    Hecker L, Vittal R, Jones T et al (2009) NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nat Med 15(9):1077–1081. doi: 10.1038/nm.2005 PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Amara N, Goven D, Prost F et al (2010) NOX4/NADPH oxidase expression is increased in pulmonary fibroblasts from patients with idiopathic pulmonary fibrosis and mediates TGFbeta1-induced fibroblast differentiation into myofibroblasts. Thorax 65(8):733–738. doi: 10.1136/thx.2009.113456 PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Barnes JL, Gorin Y (2011) Myofibroblast differentiation during fibrosis: role of NAD(P)H oxidases. Kidney Int 79(9):944–956. doi: 10.1038/ki.2010.516 PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Crestani B, Besnard V, Boczkowski J (2011) Signalling pathways from NADPH oxidase-4 to idiopathic pulmonary fibrosis. Int J Biochem Cell Biol 43(8):1086–1089. doi: 10.1016/j.biocel.2011.04.003 PubMedCrossRefGoogle Scholar
  172. 172.
    Sancho P, Mainez J, Crosas-Molist E et al (2012) NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development. PLoS One 7(9):e45285. doi: 10.1371/journal.pone.0045285 PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Jiang F, Liu GS, Dusting GJ et al (2014) NADPH oxidase-dependent redox signaling in TGF-beta-mediated fibrotic responses. Redox Biol 2:267–272. doi: 10.1016/j.redox.2014.01.012 PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Paik YH, Kim J, Aoyama T et al (2014) Role of NADPH oxidases in liver fibrosis. Antioxid Redox Signal 20(17):2854–2872. doi: 10.1089/ars.2013.5619 PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Piera-Velazquez S, Makul A, Jimenez SA (2015) Increased expression of NAPDH oxidase 4 in systemic sclerosis dermal fibroblasts: regulation by transforming growth factor beta. Arthritis Rheumatol 67(10):2749–2758. doi: 10.1002/art.39242
  176. 176.
    Spadoni T, Svegliati Baroni S, Amico D et al (2015) 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 67(6):1611–1622. doi: 10.1002/art.39084
  177. 177.
    Wang Y, Stricker HM, Gou D et al (2007) MicroRNA: past and present. Front Biosci 12:2316–2329PubMedCrossRefGoogle Scholar
  178. 178.
    Jiang X, Tsitsiou E, Herrick SE et al (2010) MicroRNAs and the regulation of fibrosis. FEBS J 277(9):2015–2021. doi: 10.1111/j.1742-4658.2010.07632.x PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Bowen T, Jenkins RH, Fraser DJ (2013) MicroRNAs, transforming growth factor beta-1, and tissue fibrosis. J Pathol 229(2):274–285. doi: 10.1002/path.4119 PubMedCrossRefGoogle Scholar
  180. 180.
    Rutnam ZJ, Wight TN, Yang BB (2013) miRNAs regulate expression and function of extracellular matrix molecules. Matrix Biol 32(2):74–85. doi: 10.1016/j.matbio.2012.11.003 PubMedCrossRefGoogle Scholar
  181. 181.
    Zhu H, Luo H, Zuo X (2013) MicroRNAs: their involvement in fibrosis pathogenesis and use as diagnostic biomarkers in scleroderma. Exp Mol Med 45:e41. doi: 10.1038/emm.2013.71 PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Babalola O, Mamalis A, Lev-Tov H et al (2013) The role of microRNAs in skin fibrosis. Arch Dermatol Res 305(9):763–776. doi: 10.1007/s00403-013-1410-1 PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Pandit KV, Milosevic J (2015) MicroRNA regulatory networks in idiopathic pulmonary fibrosis. Biochem Cell Biol 93(2):129–137. doi: 10.1139/bcb-2014-0101 PubMedCrossRefGoogle Scholar
  184. 184.
    He Y, Huang C, Zhang SP et al (2012) The potential of microRNAs in liver fibrosis. Cell Signal 24(12):2268–2272. doi: 10.1016/j.cellsig.2012.07.023 PubMedCrossRefGoogle Scholar
  185. 185.
    Srivastava SP, Koya D, Kanasaki K (2013) MicroRNAs in kidney fibrosis and diabetic nephropathy: roles on EMT and EndMT. Biomed Res Int 2013:125469. doi: 10.1155/2013/125469 PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Thum T (2014) Noncoding RNAs and myocardial fibrosis. Nat Rev Cardiol 11(11):655–663. doi: 10.1038/nrcardio.2014.125 PubMedCrossRefGoogle Scholar
  187. 187.
    Razani B, Zhang XL, Bitzer M et al (2001) Caveolin-1 regulates transforming growth factor (TGF)-beta/SMAD signaling through an interaction with the TGF-beta type I receptor. J Biol Chem 276(9):6727–6738. doi: 10.1074/jbc.M008340200 PubMedCrossRefGoogle Scholar
  188. 188.
    Del Galdo F, Lisanti MP, Jimenez SA (2008) Caveolin-1, transforming growth factor-beta receptor internalization, and the pathogenesis of systemic sclerosis. Curr Opin Rheumatol 20(6):713–719PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Gvaramia D, Blaauboer ME, Hanemaaijer R et al (2013) Role of caveolin-1 in fibrotic diseases. Matrix Biol 32(6):307–315. doi: 10.1016/j.matbio.2013.03.005
  190. 190.
    Del Galdo F, Sotgia F, de Almeida CJ et al (2008) Decreased expression of caveolin 1 in patients with systemic sclerosis: crucial role in the pathogenesis of tissue fibrosis. Arthritis Rheum 58(9):2854–2865. doi: 10.1002/art.23791
  191. 191.
    Wang XM, Zhang Y, Kim HP et al (2006) Caveolin-1: a critical regulator of lung fibrosis in idiopathic pulmonary fibrosis. J Exp Med 203(13):2895–2906. doi: 10.1084/jem.20061536 PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Tourkina E, Richard M, Gooz P et al (2008) Antifibrotic properties of caveolin-1 scaffolding domain in vitro and in vivo. Am J Physiol Lung Cell Mol Physiol 294(5):L843–L861. doi: 10.1152/ajplung.00295.2007
  193. 193.
    Jasmin JF, Mercier I, Dupuis J et al (2006) Short-term administration of a cell-permeable caveolin-1 peptide prevents the development of monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy. Circulation 114(9):912–920. doi: 10.1161/circulationaha.106.634709 PubMedCrossRefGoogle Scholar
  194. 194.
    Li Z, Wermuth PJ, Benn BS et al (2013) Caveolin-1 deficiency induces spontaneous endothelial-to-mesenchymal transition in murine pulmonary endothelial cells in vitro. Am J Pathol 182(2):325–331. doi: 10.1016/j.ajpath.2012.10.022

Copyright information

© Springer Science+Business Media LLC 2017

Authors and Affiliations

  • Joel Rosenbloom
    • 1
  • Edward Macarak
    • 1
  • Sonsoles Piera-Velazquez
    • 1
  • Sergio A. Jimenez
    • 1
  1. 1.The Joan and Joel Rosenbloom Center for Fibrotic Diseases and The Jefferson Institute of Molecular MedicineThomas Jefferson UniversityPhiladelphiaUSA

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