Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Transforming growth factor β—at the centre of systemic sclerosis

Key Points

  • Transforming growth factor β (TGF-β) superfamily members are pleotropic cytokines that regulate fibrosis, inflammation and vascular biology, all key aspects of systemic sclerosis (SSc) pathogenesis

  • Emerging data have shown that integrins, proteases and altered connective tissue sequestration can regulate activation of latent TGF-β and provide possible mechanisms for TGF-β-mediated fibrosis in SSc

  • SSc is characterized by prominent vascular features also seen in familial pulmonary arterial hypertension and hereditary haemorrhagic telangiectasia, both of which are associated with mutations in proteins involved in TGF-β and bone morphogenetic protein signalling

  • Immune cells such as dendritic cells and macrophages can activate TGF-β in SSc through surface integrins or upon ingestion of apoptotic or necrotic cells, respectively

  • Effects of TGF-β activation on immune cells include dampened T helper 1 and T helper 2 responses, increased regulatory T cell and T helper 17 cell differentiation and augmented leukocyte infiltration

Abstract

Transforming growth factor β (TGF-β) has long been implicated in fibrotic diseases, including the multisystem fibrotic disease systemic sclerosis (SSc). Expression of TGF-β-regulated genes in fibrotic skin and lungs of patients with SSc correlates with disease activity, which points to this cytokine as the central mediator of pathogenesis. Patients with SSc often develop pulmonary arterial hypertension (PAH), a particularly lethal complication caused by vascular dysfunction. Several genetic diseases with vascular features related to SSc, such as familial PAH and hereditary haemorrhagic telangiectasia, are caused by mutations in the TGF-β-sensing ALK-1 signalling pathway. These observations suggest that increased TGF-β signalling causes both vascular and fibrotic features of SSc. The question of how latent TGF-β becomes activated in local SSc tissues is, therefore, central to the understanding of SSc. Both TGF-β1 and TGF-β3 can be activated by integrins αvβ6 and αvβ8, whose upregulation in bronchial epithelial cells can activate TGF-β in SSc lungs. Other αv integrins, thrombospondin-1 or altered TGF-β sequestration by matrix proteins might be important in other target tissues. How the immune system triggers this process remains unclear, although links between inflammation and TGF-β activation are emerging. Together, these observations provide an increasingly secure framework for understanding TGF-β in SSc pathogenesis.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: TGF-β superfamily receptors.
Figure 2: TGF-β1/3 maturation and tissue sequestration.
Figure 3: Integrin-mediated activation of TGF-β.
Figure 4: TGF-β signalling mediated by TGFR-1 and ALK-1.
Figure 5: Myofibroblast progenitors.

References

  1. 1

    Shull, M. M. et al. Targeted disruption of the mouse transforming growth factor-β 1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Dickson, M. C. et al. Defective haematopoiesis and vasculogenesis in transforming growth factor-β 1 knock out mice. Development 121, 1845–1854 (1995).

    CAS  PubMed  Google Scholar 

  3. 3

    Proetzel, G. et al. Transforming growth factor-β3 is required for secondary palate fusion. Nat. Genet. 11, 409–414 (1995).

    CAS  PubMed  Google Scholar 

  4. 4

    Kaartinen, V. et al. Abnormal lung development and cleft palate in mice lacking TGF-β3 indicates defects of epithelial-mesenchymal interaction. Nat. Genet. 11, 415–421 (1995).

    CAS  PubMed  Google Scholar 

  5. 5

    Sanford, L. P. et al. TGFβ2 knockout mice have multiple developmental defects that are non-overlapping with other TGFβ knockout phenotypes. Development 124, 2659–2670 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Boileau, C. et al. TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat. Genet. 44, 916–921 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Lindsay, M. E. et al. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat. Genet. 44, 922–927 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Lowery, J. W. & de Caestecker, M. P. BMP signaling in vascular development and disease. Cytokine Growth Factor Rev. 21, 287–298 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Xu, Y., Wan, J., Jiang, D. & Wu, X. BMP-7 counteracts TGF-β1-induced epithelial-to-mesenchymal transition in human renal proximal tubular epithelial cells. J. Nephrol. 22, 403–410 (2009).

    CAS  PubMed  Google Scholar 

  10. 10

    Robertson, I. B. & Rifkin, D. B. Unchaining the beast; insights from structural and evolutionary studies on TGFβ secretion, sequestration, and activation. Cytokine Growth Factor Rev. 24, 355–372 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Kinsey, R. et al. Fibrillin-1 microfibril deposition is dependent on fibronectin assembly. J. Cell. Sci. 121, 2696–2704 (2008).

    CAS  PubMed  Google Scholar 

  12. 12

    Massam-Wu, T. et al. Assembly of fibrillin microfibrils governs extracellular deposition of latent TGFβ. J. Cell. Sci. 123, 3006–3018 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Isogai, Z. et al. Latent transforming growth factor β-binding protein 1 interacts with fibrillin and is a microfibril-associated protein. J. Biol. Chem. 278, 2750–2757 (2003).

    CAS  PubMed  Google Scholar 

  14. 14

    Zilberberg, L. et al. Specificity of latent TGF-β binding protein (LTBP) incorporation into matrix: role of fibrillins and fibronectin. J. Cell. Physiol. 227, 3828–3836 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Sfikakis, P. P. et al. Immunohistological demonstration of transforming growth factor-β isoforms in the skin of patients with systemic sclerosis. Clin. Immunol. Immunopathol. 69, 199–204 (1993).

    CAS  PubMed  Google Scholar 

  16. 16

    Higley, H. et al. Immunocytochemical localization and serologic detection of transforming growth factor β1. Association with type I procollagen and inflammatory cell markers in diffuse and limited systemic sclerosis, morphea, and Raynaud's phenomenon. Arthritis Rheum. 37, 278–288 (1994).

    CAS  PubMed  Google Scholar 

  17. 17

    Ozbilgin, M. K. & Inan, S. The roles of transforming growth factor type β3 (TGF-β3) and mast cells in the pathogenesis of scleroderma. Clin. Rheumatol. 22, 189–195 (2003).

    PubMed  Google Scholar 

  18. 18

    Dziadzio, M., Smith, R. E., Abraham, D. J., Black, C. M. & Denton, C. P. Circulating levels of active transforming growth factor β1 are reduced in diffuse cutaneous systemic sclerosis and correlate inversely with the modified Rodnan skin score. Rheumatology (Oxford) 44, 1518–1524 (2005).

    CAS  Google Scholar 

  19. 19

    Denton, C. P. et al. Recombinant human anti-transforming growth factor β1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. Arthritis Rheum. 56, 323–333 (2007).

    CAS  PubMed  Google Scholar 

  20. 20

    Christmann, R. B. et al. Association of interferon- and transforming growth factor β-regulated genes and macrophage activation with systemic sclerosis-related progressive lung fibrosis. Arthritis Rheum. 66, 714–725 (2014).

    CAS  Google Scholar 

  21. 21

    Farina, G., Lafyatis, D., Lemaire, R. & Lafyatis, R. A four-gene biomarker predicts skin disease in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum. 62, 580–588 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Kissin, E. Y., Merkel, P. A. & Lafyatis, R. Myofibroblasts and hyalinized collagen as markers of skin disease in systemic sclerosis. Arthritis Rheum. 54, 3655–3660 (2006).

    PubMed  Google Scholar 

  23. 23

    Cooper, S. M. et al. Increase in fibronectin in the deep dermis of involved skin in progressive systemic sclerosis. Arthritis Rheum. 22, 983–987 (1979).

    CAS  PubMed  Google Scholar 

  24. 24

    Fleischmajer, R., Jacobs, L., Schwartz, E. & Sakai, L. Y. Extracellular microfibrils are increased in localized and systemic scleroderma skin. Lab. Invest. 64, 791–798 (1991).

    CAS  PubMed  Google Scholar 

  25. 25

    Kissin, E. Y., Lemaire, R., Korn, J. H. & Lafyatis, R. Transforming growth factor β induces fibroblast fibrillin-1 matrix formation. Arthritis Rheum. 46, 3000–3009 (2002).

    CAS  PubMed  Google Scholar 

  26. 26

    Hasegawa, M., Sato, S. & Takehara, K. Augmented production of transforming growth factor-β by cultured peripheral blood mononuclear cells from patients with systemic sclerosis. Arch. Dermatol. Res. 296, 89–93 (2004).

    CAS  PubMed  Google Scholar 

  27. 27

    Yang, Z. et al. Absence of integrin-mediated TGFβ1 activation in vivo recapitulates the phenotype of TGFβ1-null mice. J. Cell Biol. 176, 787–793 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Araya, J., Cambier, S., Morris, A., Finkbeiner, W. & Nishimura, S. L. Integrin-mediated transforming growth factor-β activation regulates homeostasis of the pulmonary epithelial-mesenchymal trophic unit. Am. J. Pathol. 169, 405–415 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Munger, J. S. et al. The integrin αvβ6 binds and activates latent TGFβ1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96, 319–328 (1999).

    CAS  Article  Google Scholar 

  30. 30

    Annes, J. P., Chen, Y., Munger, J. S. & Rifkin, D. B. Integrin αVβ6-mediated activation of latent TGF-β requires the latent TGF-β binding protein-1. J. Cell Biol. 165, 723–734 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Horan, G. S. et al. Partial inhibition of integrin α(v)β6 prevents pulmonary fibrosis without exacerbating inflammation. Am. J. Respir. Crit. Care Med. 177, 56–65 (2008).

    CAS  PubMed  Google Scholar 

  32. 32

    Mu, D. et al. The integrin α(v)β8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-β1. J. Cell Biol. 157, 493–507 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Markovics, J. A. et al. Interleukin-1β induces increased transcriptional activation of the transforming growth factor-β-activating integrin subunit β8 through altering chromatin architecture. J. Biol. Chem. 286, 36864–36874 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Zhu, J. et al. β8 integrins are required for vascular morphogenesis in mouse embryos. Development 129, 2891–2903 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Cambier, S. et al. Integrin α(v)β8-mediated activation of transforming growth factor-β by perivascular astrocytes: an angiogenic control switch. Am. J. Pathol. 166, 1883–1894 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Mu, Z., Yang, Z., Yu, D., Zhao, Z. & Munger, J. S. TGFβ1 and TGFβ3 are partially redundant effectors in brain vascular morphogenesis. Mech. Dev. 125, 508–516 (2008).

    CAS  PubMed  Google Scholar 

  37. 37

    Travis, M. A. et al. Loss of integrin α(v)β8 on dendritic cells causes autoimmunity and colitis in mice. Nature 449, 361–365 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Asano, Y., Ihn, H., Yamane, K., Jinnin, M. & Tamaki, K. Increased expression of integrin αvβ5 induces the myofibroblastic differentiation of dermal fibroblasts. Am. J. Pathol. 168, 499–510 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Asano, Y., Ihn, H., Jinnin, M., Mimura, Y. & Tamaki, K. Involvement of αvβ5 integrin in the establishment of autocrine TGF-β signaling in dermal fibroblasts derived from localized scleroderma. J. Invest. Dermatol. 126, 1761–1769 (2006).

    CAS  PubMed  Google Scholar 

  40. 40

    Asano, Y. et al. Increased expression of integrin α(v)β3 contributes to the establishment of autocrine TGF-β signaling in scleroderma fibroblasts. J. Immunol. 175, 7708–7718 (2005).

    CAS  PubMed  Google Scholar 

  41. 41

    Henderson, N. C. et al. Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat. Med. 19, 1617–1624 (2013).

    CAS  Google Scholar 

  42. 42

    Liu, S. et al. Expression of integrin β1 by fibroblasts is required for tissue repair in vivo. J. Cell Sci. 123, 3674–3682 (2010).

    CAS  PubMed  Google Scholar 

  43. 43

    Liu, S., Kapoor, M., Denton, C. P., Abraham, D. J. & Leask, A. Loss of β1 integrin in mouse fibroblasts results in resistance to skin scleroderma in a mouse model. Arthritis Rheum. 60, 2817–2821 (2009).

    CAS  PubMed  Google Scholar 

  44. 44

    Schultz-Cherry, S. et al. Regulation of transforming growth factor-β activation by discrete sequences of thrombospondin 1. J. Biol. Chem. 270, 7304–7310 (1995).

    CAS  PubMed  Google Scholar 

  45. 45

    Crawford, S. E. et al. Thrombospondin-1 is a major activator of TGF-β1 in vivo. Cell 93, 1159–1170 (1998).

    CAS  PubMed  Google Scholar 

  46. 46

    Mimura, Y. et al. Constitutive thrombospondin-1 overexpression contributes to autocrine transforming growth factor-β signaling in cultured scleroderma fibroblasts. Am. J. Pathol. 166, 1451–1463 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Ayoubi, T. A., Meulemans, S. M., Roebroek, A. J. & Van de Ven, W. J. Production of recombinant proteins in Chinese hamster ovary cells overexpressing the subtilisin-like proprotein converting enzyme furin. Mol. Biol. Rep. 23, 87–95 (1996).

    CAS  PubMed  Google Scholar 

  48. 48

    Dubois, C. M. et al. Evidence that furin is an authentic transforming growth factor-β1-converting enzyme. Am. J. Pathol. 158, 305–316 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Bassi, D. E., Fu, J., Lopez de Cicco, R. & Klein-Szanto, A. J. Proprotein convertases: “master switches” in the regulation of tumor growth and progression. Mol. Carcinog. 44, 151–161 (2005).

    CAS  PubMed  Google Scholar 

  50. 50

    Blakytny, R. et al. Latent TGF-β1 activation by platelets. J. Cell. Physiol. 199, 67–76 (2004).

    CAS  PubMed  Google Scholar 

  51. 51

    Lyons, R. M., Gentry, L. E., Purchio, A. F. & Moses, H. L. Mechanism of activation of latent recombinant transforming growth factor β 1 by plasmin. J. Cell Biol. 110, 1361–1367 (1990).

    CAS  PubMed  Google Scholar 

  52. 52

    Jenkins, G. The role of proteases in transforming growth factor-β activation. Int. J. Biochem. Cell Biol. 40, 1068–1078 (2008).

    CAS  PubMed  Google Scholar 

  53. 53

    Guo, M., Mathieu, P. A., Linebaugh, B., Sloane, B. F. & Reiners, J. J. Jr. Phorbol ester activation of a proteolytic cascade capable of activating latent transforming growth factor-βL a process initiated by the exocytosis of cathepsin B. J. Biol. Chem. 277, 14829–14837 (2002).

    CAS  PubMed  Google Scholar 

  54. 54

    Jenkins, R. G. et al. Ligation of protease-activated receptor 1 enhances α(v)β6 integrin-dependent TGF-β activation and promotes acute lung injury. J. Clin. Invest. 116, 1606–1614 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Wang, M. et al. Matrix metalloproteinase 2 activation of transforming growth factor-β1 (TGF-β1) and TGF-β1-type II receptor signaling within the aged arterial wall. Arterioscler. Thromb. Vasc. Biol. 26, 1503–1509 (2006).

    CAS  PubMed  Google Scholar 

  56. 56

    Yu, Q. & Stamenkovic, I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-β and promotes tumor invasion and angiogenesis. Genes Dev. 14, 163–176 (2000).

    PubMed  PubMed Central  Google Scholar 

  57. 57

    Ge, G. & Greenspan, D. S. BMP1 controls TGFβ1 activation via cleavage of latent TGFβ-binding protein. J. Cell Biol. 175, 111–120 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Karsdal, M. A. et al. Matrix metalloproteinase-dependent activation of latent transforming growth factor-β controls the conversion of osteoblasts into osteocytes by blocking osteoblast apoptosis. J. Biol. Chem. 277, 44061–44067 (2002).

    CAS  PubMed  Google Scholar 

  59. 59

    Alfranca, A. et al. PGE2 induces angiogenesis via MT1-MMP-mediated activation of the TGFβ/Alk5 signaling pathway. Blood 112, 1120–1128 (2008).

    CAS  PubMed  Google Scholar 

  60. 60

    Sidhu, S. S. et al. Roles of epithelial cell-derived periostin in TGF-β activation, collagen production, and collagen gel elasticity in asthma. Proc. Natl Acad. Sci. USA 107, 14170–14175 (2010).

    CAS  PubMed  Google Scholar 

  61. 61

    Akita, K. et al. Impaired liver regeneration in mice by lipopolysaccharide via TNF-α/kallikrein-mediated activation of latent TGF-β. Gastroenterology 123, 352–364 (2002).

    CAS  PubMed  Google Scholar 

  62. 62

    Del Rosso, A. et al. Increased circulating levels of tissue kallikrein in systemic sclerosis correlate with microvascular involvement. Ann. Rheum. Dis. 64, 382–387 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Kim, W. U. et al. Elevated matrix metalloproteinase-9 in patients with systemic sclerosis. Arthritis Res. Ther. 7, R71–R79 (2005).

    CAS  PubMed  Google Scholar 

  64. 64

    Briassouli, P., Rifkin, D., Clancy, R. M. & Buyon, J. P. Binding of anti-SSA antibodies to apoptotic fetal cardiocytes stimulates urokinase plasminogen activator (uPA)/uPA receptor-dependent activation of TGF-β and potentiates fibrosis. J. Immunol. 187, 5392–5401 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Wipff, P. J., Rifkin, D. B., Meister, J. J. & Hinz, B. Myofibroblast contraction activates latent TGF-β1 from the extracellular matrix. J. Cell Biol. 179, 1311–1323 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Wipff, P. J. & Hinz, B. Integrins and the activation of latent transforming growth factor β1—an intimate relationship. Eur. J. Cell Biol. 87, 601–615 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Varga, J. & Lafyatis, R. in Hochberg: Rheumatology 6th edn Vol. 2 Ch. Etiology and Pathogenesis of Systemic Sclerosis (eds Hochberg, M. C. et al.) 1387–1402 (Mosby, 2014).

    Google Scholar 

  68. 68

    Batal, I., Domsic, R. T., Medsger, T. A. & Bastacky, S. Scleroderma renal crisis: a pathology perspective. Int. J. Rheumatol. 2010, 543704 (2010).

    PubMed  PubMed Central  Google Scholar 

  69. 69

    Dorfmuller, P. Pulmonary hypertension: pathology. Handb. Exp. Pharmacol. 218, 59–75 (2013).

    CAS  PubMed  Google Scholar 

  70. 70

    Stacher, E. et al. Modern age pathology of pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med 186, 261–272 (2012).

    PubMed  PubMed Central  Google Scholar 

  71. 71

    Cutolo, M. & Smith, V. State of the art on nailfold capillaroscopy: a reliable diagnostic tool and putative biomarker in rheumatology? Rheumatology (Oxford) 52, 1933–1940 (2013).

    Google Scholar 

  72. 72

    Berg, D. T. et al. Negative regulation of inducible nitric-oxide synthase expression mediated through transforming growth factor-β-dependent modulation of transcription factor TCF11. J. Biol. Chem. 282, 36837–36844 (2007).

    CAS  PubMed  Google Scholar 

  73. 73

    Hummers, L. K., Hall, A., Wigley, F. M. & Simons, M. Abnormalities in the regulators of angiogenesis in patients with scleroderma. J. Rheumatol. 36, 576–582 (2009).

    PubMed  PubMed Central  Google Scholar 

  74. 74

    Manetti, M. et al. Overexpression of VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, leads to insufficient angiogenesis in patients with systemic sclerosis. Circ. Res. 109, e14–e26 (2011).

    CAS  PubMed  Google Scholar 

  75. 75

    Vinores, S. A., Derevjanik, N. L., Vinores, M. A., Okamoto, N. & Campochiaro, P. A. Sensitivity of different vascular beds in the eye to neovascularization and blood-retinal barrier breakdown in VEGF transgenic mice. Adv. Exp. Med. Biol. 476, 129–138 (2000).

    CAS  PubMed  Google Scholar 

  76. 76

    Vancheeswaran, R. et al. Circulating endothelin-1 levels in systemic sclerosis subsets—a marker of fibrosis or vascular dysfunction? J. Rheumatol. 21, 1838–1844 (1994).

    CAS  PubMed  Google Scholar 

  77. 77

    Korn, J. H. et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum. 50, 3985–3993 (2004).

    CAS  PubMed  Google Scholar 

  78. 78

    Rubin, L. J. et al. Bosentan therapy for pulmonary arterial hypertension. N. Engl. J. Med 346, 896–903 (2002).

    CAS  PubMed  Google Scholar 

  79. 79

    Muller, G., Behrens, J., Nussbaumer, U., Bohlen, P. & Birchmeier, W. Inhibitory action of transforming growth factor β on endothelial cells. Proc. Natl Acad. Sci. USA 84, 5600–5604 (1987).

    CAS  PubMed  Google Scholar 

  80. 80

    Lane, K. B. et al. Heterozygous germline mutations in BMPR2, encoding a TGF-β receptor, cause familial primary pulmonary hypertension. Nat. Genet. 26, 81–84 (2000).

    CAS  PubMed  Google Scholar 

  81. 81

    Thomson, J. R. et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-β family. J. Med. Genet. 37, 741–745 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Hong, K. H. et al. Genetic ablation of the BMPR2 gene in pulmonary endothelium is sufficient to predispose to pulmonary arterial hypertension. Circulation 118, 722–730 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Frank, D. B. et al. Bone morphogenetic protein 4 promotes pulmonary vascular remodeling in hypoxic pulmonary hypertension. Circ. Res. 97, 496–504 (2005).

    CAS  PubMed  Google Scholar 

  84. 84

    Goumans, M. J. et al. Balancing the activation state of the endothelium via two distinct TGF-β type I receptors. EMBO J. 21, 1743–1753 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    David, L., Mallet, C., Mazerbourg, S., Feige, J. J. & Bailly, S. Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood 109, 1953–1961 (2007).

    CAS  PubMed  Google Scholar 

  86. 86

    Lebrin, F. et al. Endoglin promotes endothelial cell proliferation and TGF-β/ALK1 signal transduction. EMBO J. 23, 4018–4028 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Braverman, I. M., Keh, A. & Jacobson, B. S. Ultrastructure and three-dimensional organization of the telangiectases of hereditary hemorrhagic telangiectasia. J. Invest. Dermatol. 95, 422–427 (1990).

    CAS  PubMed  Google Scholar 

  88. 88

    Trembath, R. C. et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N. Engl. J. Med. 345, 325–334 (2001).

    CAS  PubMed  Google Scholar 

  89. 89

    Harrison, R. E. et al. Transforming growth factor-β receptor mutations and pulmonary arterial hypertension in childhood. Circulation 111, 435–441 (2005).

    CAS  PubMed  Google Scholar 

  90. 90

    Scharpfenecker, M. et al. BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis. J. Cell Sci. 120, 964–972 (2007).

    CAS  PubMed  Google Scholar 

  91. 91

    Koumakis, E. et al. TGFβ receptor gene variants in systemic sclerosis-related pulmonary arterial hypertension: results from a multicentre EUSTAR study of European Caucasian patients. Ann. Rheum. Dis. 71, 1900–1903 (2012).

    CAS  PubMed  Google Scholar 

  92. 92

    Fujimoto, M. et al. A clue for telangiectasis in systemic sclerosis: elevated serum soluble endoglin levels in patients with the limited cutaneous form of the disease. Dermatology 213, 88–92 (2006).

    CAS  PubMed  Google Scholar 

  93. 93

    Nabel, E. G. et al. Direct transfer of transforming growth factor β 1 gene into arteries stimulates fibrocellular hyperplasia. Proc. Natl Acad. Sci. USA 90, 10759–10763 (1993).

    CAS  PubMed  Google Scholar 

  94. 94

    Derrett-Smith, E. C. et al. Endothelial injury in a transforming growth factor β-dependent mouse model of scleroderma induces pulmonary arterial hypertension. Arthritis Rheum. 65, 2928–2939 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Lawler, P. R. & Lawler, J. Molecular basis for the regulation of angiogenesis by thrombospondin-1 and -2. Cold Spring Harb. Perspect. Med. 2, a006627 (2012).

    PubMed  PubMed Central  Google Scholar 

  96. 96

    Roberts, A. B. et al. Type β transforming growth factor: a bifunctional regulator of cellular growth. Proc. Natl Acad. Sci. USA 82, 119–123 (1985).

    CAS  PubMed  Google Scholar 

  97. 97

    Roberts, A. B. et al. Transforming growth factor type β: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc. Natl Acad. Sci. USA 83, 4167–4171 (1986).

    CAS  PubMed  Google Scholar 

  98. 98

    Roberts, A. B., Heine, U. I., Flanders, K. C. & Sporn, M. B. Transforming growth factor-β. Major role in regulation of extracellular matrix. Ann. NY Acad. Sci. 580, 225–232 (1990).

    CAS  PubMed  Google Scholar 

  99. 99

    Penttinen, R. P., Kobayashi, S. & Bornstein, P. Transforming growth factor β increases mRNA for matrix proteins both in the presence and in the absence of changes in mRNA stability. Proc. Natl Acad. Sci. USA 85, 1105–1108 (1988).

    CAS  PubMed  Google Scholar 

  100. 100

    Friedman, S. L., Sheppard, D., Duffield, J. S. & Violette, S. Therapy for fibrotic diseases: nearing the starting line. Sci. Transl. Med. 5, 167sr1 (2013).

    PubMed  Google Scholar 

  101. 101

    Higashiyama, H. et al. Inhibition of activin receptor-like kinase 5 attenuates bleomycin-induced pulmonary fibrosis. Exp. Mol. Pathol. 83, 39–46 (2007).

    CAS  PubMed  Google Scholar 

  102. 102

    Zhang, Y., McCormick, L. L. & Gilliam, A. C. Latency-associated peptide prevents skin fibrosis in murine sclerodermatous graft-versus-host disease, a model for human scleroderma. J. Invest. Dermatol. 121, 713–719 (2003).

    CAS  PubMed  Google Scholar 

  103. 103

    Gabbiani, G. The myofibroblast in wound healing and fibrocontractive diseases. J. Pathol. 200, 500–503 (2003).

    CAS  PubMed  Google Scholar 

  104. 104

    Iwano, M. et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J. Clin. Invest. 110, 341–350 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Kim, K. K. et al. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc. Natl Acad. Sci. USA 103, 13180–13185 (2006).

    CAS  PubMed  Google Scholar 

  106. 106

    Humphreys, B. D. et al. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am. J. Pathol. 176, 85–97 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Wu, C. F. et al. Transforming growth factor β-1 stimulates profibrotic epithelial signaling to activate pericyte-myofibroblast transition in obstructive kidney fibrosis. Am. J. Pathol. 182, 118–131 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Hung, C. et al. Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 188, 820–830 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Dulauroy, S., Di Carlo, S. E., 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. 18, 1262–1270 (2012).

    CAS  PubMed  Google Scholar 

  110. 110

    Goritz, C. et al. A pericyte origin of spinal cord scar tissue. Science 333, 238–242 (2011).

    PubMed  Google Scholar 

  111. 111

    LeBleu, V. S. et al. Origin and function of myofibroblasts in kidney fibrosis. Nat. Med. 19, 1047–1053 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Rajkumar, V. S., Sundberg, C., Abraham, D. J., Rubin, K. & Black, C. M. Activation of microvascular pericytes in autoimmune Raynaud's phenomenon and systemic sclerosis. Arthritis Rheum. 42, 930–941 (1999).

    CAS  PubMed  Google Scholar 

  113. 113

    Desmoulière, A., Geinoz, A., Gabbiani, F. & Gabbiani, G. Transforming growth factor-β 1 induces α-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J. Cell Biol. 122, 103–111 (1993).

    PubMed  Google Scholar 

  114. 114

    Willis, B. C. et al. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-β1: potential role in idiopathic pulmonary fibrosis. Am. J. Pathol. 166, 1321–1332 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Farina, G. et al. Cartilage oligomeric matrix protein expression in systemic sclerosis reveals heterogeneity of dermal fibroblast responses to transforming growth factor β. Ann. Rheum. Dis. 68, 435–441 (2009).

    CAS  PubMed  Google Scholar 

  116. 116

    Lemaire, R., Bayle, J. & Lafyatis, R. Fibrillin in Marfan syndrome and tight skin mice provides new insights into transforming growth factor-β regulation and systemic sclerosis. Curr. Opin. Rheumatol. 18, 582–587 (2006).

    CAS  PubMed  Google Scholar 

  117. 117

    Neptune, E. R. et al. Dysregulation of TGF-β activation contributes to pathogenesis in Marfan syndrome. Nat. Genet. 33, 407–411 (2003).

    CAS  PubMed  Google Scholar 

  118. 118

    Loeys, B. L. et al. Mutations in fibrillin-1 cause congenital scleroderma: stiff skin syndrome. Sci. Transl. Med. 2, 23ra20 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Gerber, E. E. et al. Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma. Nature 503, 126–130 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Morris, E. et al. Endoglin promotes TGF-β/Smad1 signaling in scleroderma fibroblasts. J. Cell. Physiol. 226, 3340–3348 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Pannu, J., Nakerakanti, S., Smith E, ten Dijke, P. & Trojanowska, M. Transforming growth factor-β receptor type I-dependent fibrogenic gene program is mediated via activation of Smad1 and ERK1/2 pathways. J. Biol. Chem. 282, 10405–10413 (2007).

    CAS  PubMed  Google Scholar 

  122. 122

    Nakerakanti, S. S., Bujor, A. M. & Trojanowska, M. CCN2 is required for the TGF-β induced activation of Smad1-Erk1/2 signaling network. PLoS ONE 6, e21911 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Chen, Y. et al. Contribution of activin receptor-like kinase 5 (transforming growth factor β receptor type I) signaling to the fibrotic phenotype of scleroderma fibroblasts. Arthritis Rheum. 54, 1309–1316 (2006).

    CAS  PubMed  Google Scholar 

  124. 124

    Bhattacharyya, S. et al. Smad-independent transforming growth factor-β regulation of early growth response-1 and sustained expression in fibrosis: implications for scleroderma. Am. J. Pathol. 173, 1085–1099 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Wu, M. et al. Essential roles for early growth response transcription factor Egr-1 in tissue fibrosis and wound healing. Am. J. Pathol. 175, 1041–1055 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Bhattacharyya, S. et al. A non-Smad mechanism of fibroblast activation by transforming growth factor-β via c-Abl and Egr-1: selective modulation by imatinib mesylate. Oncogene 28, 1285–1297 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Trojanowska, M. Noncanonical transforming growth factor β signaling in scleroderma fibrosis. Curr. Opin. Rheumatol. 21, 623–629 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Varga, J. & Abraham, D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J. Clin. Invest. 117, 557–567 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Derunck, R. & Miyazono, K. (Eds) The TGF-β Family 8th edn (Cold Spring Harbor Laboratory Press, 2007).

    Google Scholar 

  130. 130

    Mayes, M. D. et al. Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis. Am. J. Hum. Genet. 94, 47–61 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    York, M. R. et al. A macrophage marker, Siglec-1, is increased on circulating monocytes in patients with systemic sclerosis and induced by type I interferons and toll-like receptor agonists. Arthritis Rheum. 56, 1010–1020 (2007).

    CAS  PubMed  Google Scholar 

  132. 132

    Worthington, J. J., Fenton, T. M., Czajkowska, B. I., Klementowicz, J. E. & Travis, M. A. Regulation of TGFβ in the immune system: an emerging role for integrins and dendritic cells. Immunobiology 217, 1259–1265 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Hahm, K. et al. αv β6 integrin regulates renal fibrosis and inflammation in Alport mouse. Am. J. Pathol. 170, 110–125 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Puthawala, K. et al. Inhibition of integrin α(v)β6, an activator of latent transforming growth factor-β, prevents radiation-induced lung fibrosis. Am. J. Respir. Crit. Care Med. 177, 82–90 (2008).

    CAS  PubMed  Google Scholar 

  135. 135

    Kitamura, H. et al. Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin αvβ8-mediated activation of TGF-β. J. Clin. Invest. 121, 2863–2875 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Lee, C. G. et al. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor β(1). J. Exp. Med. 194, 809–821 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Fox, S. W., Fuller, K., Bayley, K. E., Lean, J. M. & Chambers, T. J. TGF-β 1 and IFN-gamma direct macrophage activation by TNF-α to osteoclastic or cytocidal phenotype. J. Immunol. 165, 4957–4963 (2000).

    CAS  PubMed  Google Scholar 

  138. 138

    Korns, D., Frasch, S. C., Fernandez-Boyanapalli, R., Henson, P. M. & Bratton, D. L. Modulation of macrophage efferocytosis in inflammation. Front. Immunol. 2, 57 (2011).

    PubMed  PubMed Central  Google Scholar 

  139. 139

    Lucas, M., Stuart, L. M., Savill, J. & Lacy-Hulbert, A. Apoptotic cells and innate immune stimuli combine to regulate macrophage cytokine secretion. J. Immunol. 171, 2610–2615 (2003).

    CAS  PubMed  Google Scholar 

  140. 140

    Huynh, M. L., Fadok, V. A. & Henson, P. M. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-β1 secretion and the resolution of inflammation. J. Clin. Invest. 109, 41–50 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Edwards, J. P. et al. Regulation of the expression of GARP/latent TGF-β1 complexes on mouse T cells and their role in regulatory T cell and Th17 differentiation. J. Immunol. 190, 5506–5515 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Radstake, T. R. et al. Increased frequency and compromised function of T regulatory cells in systemic sclerosis (SSc) is related to a diminished CD69 and TGFβ expression. PLoS ONE 4, e5981 (2009).

    PubMed  PubMed Central  Google Scholar 

  143. 143

    Radstake, T. R. et al. The pronounced Th17 profile in systemic sclerosis (SSc) together with intracellular expression of TGFβ and IFNgamma distinguishes SSc phenotypes. PLoS ONE 4, e5903 (2009).

    PubMed  PubMed Central  Google Scholar 

  144. 144

    Wahl, S. M. et al. Transforming growth factor type β induces monocyte chemotaxis and growth factor production. Proc. Natl Acad. Sci. USA 84, 5788–5792 (1987).

    CAS  PubMed  Google Scholar 

  145. 145

    Li, A. G., Wang, D., Feng, X. H. & Wang, X. J. Latent TGFβ1 overexpression in keratinocytes results in a severe psoriasis-like skin disorder. EMBO J. 23, 1770–1781 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Fitch, E. L. et al. Inflammatory skin disease in K5.hTGF-β1 transgenic mice is not dependent on the IL-23/Th17 inflammatory pathway. J. Invest. Dermatol. 129, 2443–2450 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    Mathes, A. L. et al. Global chemokine expression in systemic sclerosis (SSc): CCL19 expression correlates with vascular inflammation in SSc skin. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2012-202814 (2013).

  148. 148

    Aluwihare, P. et al. Mice that lack activity of αvβ6- and αvβ8-integrins reproduce the abnormalities of Tgfb1- and Tgfb3-null mice. J. Cell Sci. 122, 227–232 (2009).

    CAS  PubMed  Google Scholar 

  149. 149

    Sonnylal, S. et al. Selective expression of connective tissue growth factor in fibroblasts in vivo promotes systemic tissue fibrosis. Arthritis Rheum. 62, 1523–1532 (2010).

    PubMed  Google Scholar 

  150. 150

    Parada, C., Li, J., Iwata, J., Suzuki, A. & Chai, Y. CTGF mediates Smad-dependent transforming growth factor β signaling to regulate mesenchymal cell proliferation during palate development. Mol. Cell. Biol. 33, 3482–3493 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

    Lee, C. H., Shah, B., Moioli, E. K. & Mao, J. J. CTGF directs fibroblast differentiation from human mesenchymal stem/stromal cells and defines connective tissue healing in a rodent injury model. J. Clin. Invest. 120, 3340–3349 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Tan, J. T. et al. Connective tissue growth factor inhibits adipocyte differentiation. Am. J. Physiol. Cell Physiol. 295, C740–C751 (2008).

    CAS  PubMed  Google Scholar 

  153. 153

    Wu, S. et al. ALK-5 mediates endogenous and TGF-β1-induced expression of connective tissue growth factor in embryonic lung. Am. J. Respir. Cell Mol. Biol. 36, 552–561 (2007).

    CAS  PubMed  Google Scholar 

  154. 154

    Leivonen, S. K., Häkkinen, L., Liu, D. & Kähäri, V. M. Smad3 and extracellular signal-regulated kinase 1/2 coordinately mediate transforming growth factor-β-induced expression of connective tissue growth factor in human fibroblasts. J. Invest. Dermatol. 124, 1162–1169 (2005).

    CAS  PubMed  Google Scholar 

  155. 155

    Huang, W. T., Vayalil, P. K., Miyata, T., Hagood, J. & Liu, R. M. Therapeutic value of small molecule inhibitor to plasminogen activator inhibitor-1 for lung fibrosis. Am. J. Respir. Cell Mol. Biol. 46, 87–95 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156

    Ghosh, A. K. et al. Genetic deficiency of plasminogen activator inhibitor-1 promotes cardiac fibrosis in aged mice: involvement of constitutive transforming growth factor-β signaling and endothelial-to-mesenchymal transition. Circulation 122, 1200–1209 (2010).

    CAS  PubMed  Google Scholar 

  157. 157

    Herrera, B. et al. Source of early reactive oxygen species in the apoptosis induced by transforming growth factor-β in fetal rat hepatocytes. Free Radic. Biol. Med. 36, 16–26 (2004).

    CAS  PubMed  Google Scholar 

  158. 158

    Dooley, A. et al. Modulation of collagen type I, fibronectin and dermal fibroblast function and activity, in systemic sclerosis by the antioxidant epigallocatechin-3-gallate. Rheumatology (Oxford) 49, 2024–2036 (2010).

    CAS  Google Scholar 

  159. 159

    Jarman, E. R. et al. An inhibitor of NADPH oxidase-4 attenuates established pulmonary fibrosis in a rodent disease model. Am. J. Respir. Cell Mol. Biol. 50, 158–169 (2014).

    PubMed  Google Scholar 

  160. 160

    Wu, M. et al. Identification of cadherin 11 as a mediator of dermal fibrosis and possible role in systemic sclerosis. Arthritis Rheum. 66, 1010–1021 (2014).

    CAS  Google Scholar 

  161. 161

    Getsios, S., Chen, G. T., Huang, D. T. & MacCalman, C. D. Regulated expression of cadherin-11 in human extravillous cytotrophoblasts undergoing aggregation and fusion in response to transforming growth factor β1. J. Reprod. Fertil. 114, 357–363 (1998).

    CAS  PubMed  Google Scholar 

  162. 162

    Schneider, D. J. et al. Cadherin-11 contributes to pulmonary fibrosis: potential role in TGF-β production and epithelial to mesenchymal transition. FASEB J. 26, 503–512 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. 163

    Shi-wen, X. et al. Endothelin is a downstream mediator of profibrotic responses to transforming growth factor β in human lung fibroblasts. Arthritis Rheum. 56, 4189–4194 (2007).

    PubMed  Google Scholar 

  164. 164

    Lambers, C. et al. The interaction of endothelin-1 and TGF-β1 mediates vascular cell remodeling. PLoS ONE 8, e73399 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165

    King, T. E. et al. BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 184, 92–99 (2011).

    PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Robert Lafyatis.

Ethics declarations

Competing interests

R.L. declares that he has acted as a consultant for Actelion, Akros, Amira, Biogen, Bristol Myers Squibb, Celdara, Celgene, Celltex, Dart Therapeutics, EMD Serono, Genentech, Genzyme, Idera, Inception, Intermune, Lycera, Medimmune, Novartis, Precision Dermatology, PRISM, Promedior, Regeneron, Roche, Sanofi, Aventis, Shire, UCB and Zwitter, and that he has received grants from Genentech, Genzyme, Human Genome Sciences, Regeneron, Sanofi, Shire, and UCB.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lafyatis, R. Transforming growth factor β—at the centre of systemic sclerosis. Nat Rev Rheumatol 10, 706–719 (2014). https://doi.org/10.1038/nrrheum.2014.137

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing