Top

Published in:

01-08-2006 | Review

Scar wars: is TGFβ the phantom menace in scleroderma?

Published in: Arthritis Research & Therapy | Issue 4/2006

Abstract

The autoimmune disease scleroderma (systemic sclerosis (SSc)) is characterized by extensive tissue fibrosis, causing significant morbidity. There is no therapy for the fibrosis observed in SSc; indeed, the underlying cause of the scarring observed in this disease is unknown. Transforming growth factor-β (TGFβ) has long been hypothesized to be a major contributor to pathological fibrotic diseases, including SSc. Recently, the signaling pathways through which TGFβ activates a fibrotic program have been elucidated and, as a consequence, several possible points for anti-fibrotic drug intervention in SSc have emerged.

Available only for authorised users

Eckes B, Zigrino P, Kessler D, Holtkotter O, Shephard P, Mauch C, Krieg T: Fibroblast-matrix interactions in wound healing andfibrosis. Matrix Biol. 2000, 19: 325-332. 10.1016/S0945-053X(00)00077-9.CrossRefPubMed

Gabbiani G: The myofibroblast in wound healing and fibro-contractive diseases. J Pathol. 2003, 200: 500-503. 10.1002/path.1427.CrossRefPubMed

Bedossa P, Paradis V: Liver extracellular matrix in health and disease. J Pathol. 2003, 200: 504-515. 10.1002/path.1397.CrossRefPubMed

Fogo AB: Mesangial matrix modulation and glomerulosclerosis. Exp Nephrol. 1999, 7: 147-159. 10.1159/000020595.CrossRefPubMed

LeRoy EC, Trojanowska MI, Smith EA: Cytokines and humanfibrosis. Eur Cytokine Netw. 1990, 1: 215-219.PubMed

Steen VD, Medsger TA: Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum. 2000, 43: 2437-2444. 10.1002/1529-0131(200011)43:11<2437::AID-ANR10>3.0.CO;2-U.CrossRefPubMed

Kane CJ, Hebda PA, Mansbridge JN, Hanawalt PC: Direct evidence for spatial and temporal regulation of transforming growth factor beta 1 expression during cutaneous wound healing. Cell Physiol. 1991, 148: 157-173. 10.1002/jcp.1041480119.CrossRef

McCartney-Francis NL, Frazier-Jessen M, Wahl SM: TGF-beta: a balancing act. Int Rev Immunol. 1998, 16: 553-580.CrossRefPubMed

Massague J: TGF-beta signal transduction. Annu Rev Biochem. 1998, 67: 753-791. 10.1146/annurev.biochem.67.1.753.CrossRefPubMed

10.

Leask A, Abraham DJ: TGF-beta signaling and the fibrotic response. FASEB J. 2004, 18: 816-827. 10.1096/fj.03-1273rev.CrossRefPubMed

11.

Roberts AB: TGF-beta signaling from receptors to thenucleus. Microbes Infect. 1999, 1: 1265-1273. 10.1016/S1286-4579(99)00258-0.CrossRefPubMed

12.

Zawel L, Dai JL, Buckhaults P, Zhou S, Kinzler KW, Vogelstein B, Kern SE: Human Smad3 and Smad4 are sequence-specific transcription activators. Mol Cell. 1998, 1: 611-617. 10.1016/S1097-2765(00)80061-1.CrossRefPubMed

13.

Liu B, Dou CL, Prabhu L, Lai E: FAST-2 is a mammalian winged-helix protein which mediates transforming growth factor betasignals. Mol Cell Biol. 1999, 19: 424-430.PubMedCentralCrossRefPubMed

14.

Nakao A, Afrakhte M, Moren A, Nakayama T, Christian JL, Heuchel R, Itoh S, Kawabata M, Heldin NE, Heldin CH, ten Dijke P: Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature. 1997, 389: 631-635. 10.1038/39369.CrossRefPubMed

15.

von Gersdorff G, Susztak K, Rezvani F, Bitzer M, Liang D, Bottinger EP: Smad3 and Smad4 mediate transcriptional activation of the human Smad7 promoter by transforming growth factor beta. J BiolChem. 2000, 275: 11320-11326.

16.

Chen Y, Blom IE, Sa S, Goldschmeding R, Abraham DJ, Leask A: CTGF expression in mesangial cells: involvement of SMADs, MAP kinase, and PKC. Kidney Int. 2002, 62: 1149-1159. 10.1111/j.1523-1755.2002.kid567.x.CrossRefPubMed

17.

Leask A, Holmes A, Black CM, Abraham DJ: CTGF generegulation: requirements for its induction by TGFβ in fibroblasts. J Biol Chem. 2003, 278: 13008-13015. 10.1074/jbc.M210366200.CrossRefPubMed

18.

Stratton R, Rajkumar V, Ponticos M, Nichols B, Shiwen X, Black CM, Abraham DJ, Leask A: Prostacyclin derivatives prevent the fibrotic response to TGF-beta by inhibiting the Ras/MEK/ERK pathway. FASEB J. 2002, 16: 1949-1951.PubMed

19.

Mustoe TA, Pierce GF, Thomason A, Gramates P, Sporn MB, Deuel TF: Accelerated healing of incisional wounds in rats induced by transforming growth factor-beta. Science. 1987, 237: 1333-1336.CrossRefPubMed

20.

Lin RY, Sullivan KM, Argenta PA, Meuli M, Lorenz HP, Adzick NS: Exogenous transforming growth factor-beta amplifies its own expression and induces scar formation in a model of human fetal skinrepair. Ann Surg. 1995, 222: 146-154.PubMedCentralCrossRefPubMed

21.

Duncan MR, Frazier KS, Abramson S, Williams S, Klapper H, Huang X, Grotendorst GR: Connective tissue growth factor mediates transforming growth factor beta-induced collagen synthesis: down-regulation by cAMP. FASEB J. 1999, 13: 1774-1786.PubMed

22.

Mori T, Kawara S, Shinozaki M, Hayashi N, Kakinuma T, Igarashi A, Takigawa M, Nakanishi T, Takehara K: Role and interaction of connective tissue growth factor with transforming growth factor-beta in persistent fibrosis: A mouse fibrosis model. J Cell Physiol. 1999, 181: 153-159. 10.1002/(SICI)1097-4652(199910)181:1<153::AID-JCP16>3.0.CO;2-K.CrossRefPubMed

23.

Shah M, Foreman DM, Ferguson MW: Neutralising antibody to TGF-beta 1,2 reduces cutaneous scarring in adult rodents. J Cell Sci. 1994, 107: 1137-1157.PubMed

24.

Cordeiro MF, Mead A, Ali RR, Alexander RA, Murray S, Chen C, York-Defalco C, Dean NM, Schultz GS, Khaw PT: Novel anti-sense oligonucleotides targeting TGF-beta inhibit in vivo scarring and improve surgical outcome. Gene Ther. 2003, 10: 59-71. 10.1038/sj.gt.3301865.CrossRefPubMed

25.

Kulkarni AB, Karlsson S: Transforming growth factor-beta 1 knockout mice. A mutation in one cytokine gene causes a dramatic inflammatorydisease. Am J Pathol. 1993, 143: 3-9.PubMedCentralPubMed

26.

Bottinger EP, Letterio JJ, Roberts AB: Biology of TGF-beta in knockout and transgenic mouse models. Kidney Int. 1997, 51: 1355-1360.CrossRefPubMed

27.

Reiss M: TGF-beta and cancer. Microbes Infect. 1999, 1: 1327-1347. 10.1016/S1286-4579(99)00251-8.CrossRefPubMed

28.

McWhirter A, Colosetti P, Rubin K, Miyazono K, Black C: Collagen type I is not under autocrine control by transforming growth factor-beta 1 in normal and scleroderma fibroblasts. Lab Invest. 1994, 71: 885-894.PubMed

29.

Querfeld C, Eckes B, Huerkamp C, Krieg T, Sollberg S: Expression of TGF-beta 1, -beta 2 and -beta 3 in localized and systemicscleroderma. J Dermatol Sci. 1999, 21: 13-22. 10.1016/S0923-1811(99)00008-0.CrossRefPubMed

30.

Snowden N, Coupes B, Herrick A, Illingworth K, Jayson MI, Brenchley PE: Plasma TGF beta in systemic sclerosis: a cross-sectionalstudy. Ann Rheum Dis. 1994, 53: 763-767.PubMedCentralCrossRefPubMed

31.

Dziadzio M, Smith RE, Abraham DJ, Black CM, Denton CP: Circulating levels of active transforming growth factor beta1 are reduced in diffuse cutaneous systemic sclerosis and correlate inversely with the modified Rodnan skin score. Rheumatology. 2005, 44: 1518-1524. 10.1093/rheumatology/kei088.CrossRefPubMed

32.

Ihn H, Yamane K, Kubo M, Tamaki K: Blockade of endogenous transforming growth factor beta signaling prevents up-regulated collagen synthesis in scleroderma fibroblasts: association with increased expression of transforming growth factor beta receptors. ArthritisRheum. 2001, 244: 474-478.CrossRef

33.

Pannu J, Gore-Hyer E, Yamanaka M, Smith EA, Rubinchik S, Dong JY, Jablonska S, Blaszczyk M, Trojanowska M: An increased transforming growth factor beta receptor type I: type II ratio contributes to elevated collagen protein synthesis that is resistant to inhibition via a kinase-deficient transforming growth factor beta receptor type II in scleroderma. Arthritis Rheum. 2004, 50: 1566-1577. 10.1002/art.20225.CrossRefPubMed

34.

Chen Y, Shiwen X, Eastwood M, Black CM, Denton CP, Leask A, Abraham DJ: ALK5 (TGFβ receptor type I) signaling contributes to the fibrotic phenotype of scleroderma fibroblasts. Arthritis Rheum. 2006, 54: 1309-1316. 10.1002/art.21725.CrossRefPubMed

35.

Chen Y, Shiwen X, van Beek J, Kennedy L, McLeod M, Renzoni EA, Bou-Gharios G, Wilcox-Adelman S, Goetinck PF, Eastwood M, Black CM, Abraham DJ, Leask A: Matrix contraction by dermal fibroblasts requires TGFbeta/ALK5, heparan sulfate containing proteoglycans and MEK/ERK: Insights into pathological scarring in chronic fibrotic disease. Am J Pathol. 2005, 167: 1699-1711.PubMedCentralCrossRefPubMed

36.

Larsson J, Goumans M, Sjöstrand LJ, van Rooijen MA, Ward D, Levéen P, Xu X, ten Dijke P, Mummery CL, Karlsson S: Abnormal angiogenesis but intact hematopoietic potential in TGF-β type I receptor-deficient mice. EMBO J. 2001, 20: 1663-1673. 10.1093/emboj/20.7.1663.PubMedCentralCrossRefPubMed

37.

Ashcroft GS, Yang X, Glick AB, Weinstein M, Letterio JL, Mizel DE, Anzano M, Greenwell-Wild T, Wahl SM, Deng C, Roberts AB: Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol. 1999, 1: 260-266. 10.1038/12971.CrossRefPubMed

38.

Flanders KC, Sullivan CD, Fujii M, Sowers A, Anzano MA, Arabshahi A, Major C, Deng C, Russo A, Mitchell JB, Roberts AB: Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation. Am J Pathol. 2002, 160: 1057-1068.PubMedCentralCrossRefPubMed

39.

Lakos G, Takagawa S, Chen SJ, Ferreira AM, Han G, Masuda K, Wang XJ, DiPietro LA, Varga J: Targeted disruption of TGF-beta/Smad3 signaling modulates skin fibrosis in a mouse model of scleroderma. Am J Pathol. 2004, 165: 203-217.PubMedCentralCrossRefPubMed

40.

Holmes A, Abraham DJ, Sa S, Shiwen X, Black CM, Leask A: CTGF and SMADs, maintenance of scleroderma phenotype is independent of SMAD signaling. J Biol Chem. 2001, 276: 10594-10601. 10.1074/jbc.M010149200.CrossRefPubMed

41.

Yang YC, Piek E, Zavadil J, Liang D, Xie D, Heyer J, Pavlidis P, Kucherlapati R, Roberts AB, Bottinger EP: Hierarchical model of gene regulation by transforming growth factor beta. Proc Natl Acad Sci USA. 2003, 100: 10269-10274. 10.1073/pnas.1834070100.PubMedCentralCrossRefPubMed

42.

Verrecchia F, Chu ML, Mauviel A: Identification of novel TGF-beta/Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach. J Biol Chem. 2001, 276: 17058-17062. 10.1074/jbc.M100754200.CrossRefPubMed

43.

Yang X, Letterio JJ, Lechleider RJ, Chen L, Hayman R, Gu H, Roberts AB, Deng C: Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta. EMBO J. 1999, 18: 1280-1291. 10.1093/emboj/18.5.1280.PubMedCentralCrossRefPubMed

44.

Borton AJ, Frederick JP, Datto MB, Wang XF, Weinstein RS: The loss of Smad3 results in a lower rate of bone formation and osteopenia through dysregulation of osteoblast differentiation and apoptosis. J Bone Miner Res. 2001, 16: 1754-1764. 10.1359/jbmr.2001.16.10.1754.CrossRefPubMed

45.

Mori Y, Chen SJ, Varga J: Expression and regulation of intra-cellular SMAD signaling in scleroderma skin fibroblasts. Arthritis Rheum. 2003, 48: 1964-1978. 10.1002/art.11157.CrossRefPubMed

46.

Mimura Y, Ihn H, Jinnin M, Asano Y, Yamane K, Tamaki K: Constitutive thrombospondin-1 overexpression contributes to autocrine transforming growth factor-beta signaling in cultured scleroderma fibroblasts. Am J Pathol. 2005, 166: 1451-1463.PubMedCentralCrossRefPubMed

47.

Leask A, Abraham DJ, Finlay DR, Holmes A, Pennington D, Shi-Wen X, Chen Y, Venstrom K, Dou X, Ponticos M, et al: Dysregulation of transforming growth factor beta signaling in scleroderma: over-expression of endoglin in cutaneous scleroderma fibroblasts. Arthritis Rheum. 2002, 46: 1857-1865. 10.1002/art.10333.CrossRefPubMed

48.

Dong C, Zhu S, Wang T, Yoon W, Li Z, Alvarez RJ, ten Dijke P, White B, Wigley FM, Goldschmidt-Clermont PJ: Deficient Smad7 expression: a putative molecular defect in scleroderma. Proc Natl Acad Sci USA. 2002, 99: 3908-3913. 10.1073/pnas.062010399.PubMedCentralCrossRefPubMed

49.

Asano Y, Ihn H, Yamane K, Kubo M, Tamaki K: Impaired Smad7-Smurf-mediated negative regulation of TGF-beta signaling in scleroderma fibroblasts. J Clin Invest. 2004, 113: 253-264. 10.1172/JCI200416269.PubMedCentralCrossRefPubMed

50.

Kikuchi K, Hartl CW, Smith EA, LeRoy EC, Trojanowska M: Direct demonstration of transcriptional activation of collagen gene expression in systemic sclerosis fibroblasts: insensitivity to TGF beta 1 stimulation. Biochem Biophys Res Commun. 1992, 187: 45-50. 10.1016/S0006-291X(05)81456-1.CrossRefPubMed

51.

Echtermeyer F, Streit M, Wilcox-Adelman S, Saoncella S, Denhez F, Detmar M, Goetinck P: Delayed wound repair and impaired angiogenesis in mice lacking syndecan-4. J Clin Invest. 2001, 107: R9-R14.PubMedCentralCrossRefPubMed

52.

Wilcox-Adelman SA, Denhez F, Goetinck PF: Syndecan-4 modulates focal adhesion kinase phosphorylation. J Biol Chem. 2002, 277: 32970-32977. 10.1074/jbc.M201283200.CrossRefPubMed

53.

Thannickal VJ, Lee DY, White ES, Cui Z, Larios JM, Chacon R, Horowitz JC, Day RM, Thomas PE: Myofibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. J Biol Chem. 2003, 278: 12384-12389. 10.1074/jbc.M208544200.CrossRefPubMed

54.

Serini G, Bochaton-Piallat ML, Ropraz P, Geinoz A, Borsi L, Zardi L, Gabbiani G: The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growthfactor-beta1. J Cell Biol. 1998, 142: 873-881. 10.1083/jcb.142.3.873.PubMedCentralCrossRefPubMed

55.

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: 886-892. 10.1111/j.0022-202X.2005.23701.x.CrossRefPubMed

56.

Bork P: The modular architecture of a new family of growth regulators related to connective tissue growth factor. FEBS Lett. 1993, 327: 125-130. 10.1016/0014-5793(93)80155-N.CrossRefPubMed

57.

Perbal B: CCN proteins: multifunctional signalling regulators. Lancet. 2004, 363: 62-64. 10.1016/S0140-6736(03)15172-0.CrossRefPubMed

58.

Van Beek JP, Kennedy L, Rockel JS, Bernier SM, Leask A: The induction of CCN2 by TGFbeta1 involves Ets-1. Arthritis Res Ther. 2006, 8: R36-10.1186/ar1890.PubMedCentralCrossRefPubMed

59.

Dziadzio M, Usinger W, Leask A, Abraham D, Black CM, Denton C, Stratton R: N-terminal connective tissue growth factor is a marker of the fibrotic phenotype in scleroderma. QJM. 2005, 98: 485-492. 10.1093/qjmed/hci078.CrossRefPubMed

60.

Roestenberg P, van Nieuwenhoven FA, Wieten L, Boer P, Diekman T, Tiller AM, Wiersinga WM, Oliver N, Usinger W, Weitz S, et al: Connective tissue growth factor is increased in plasma of type 1 diabetic patients with nephropathy. Diabetes Care. 2004, 27: 1164-1170.CrossRefPubMed

61.

Shi-Wen X, Stanton L, Kennedy L, Pala D, Chen Y, Howat SL, Renzoni EA, Carter DE, Bou-Gharios G, Stratton R, et al: CCN2 is necessary for adhesive responses to TGFbeta 1 in embryonicfibroblasts. J Biol Chem. 2006, 281: 10715-10726. 10.1074/jbc.M511343200.CrossRefPubMed

62.

Chen Y, Abraham DJ, Shi-Wen X, Pearson JD, Black CM, Lyons KM, Leask A: CCN2 (connective tissue growth factor) promotes fibroblast adhesion to fibronectin. Mol Biol Cell. 2004, 15: 5635-5646. 10.1091/mbc.E04-06-0490.PubMedCentralCrossRefPubMed

63.

Babic AM, Chen CC, Lau LF: Fisp12/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin alphavbeta3, promotes endothelial cell survival, and induces angiogenesis in vivo. Mol Cell Biol. 1999, 19: 2958-2966.PubMedCentralCrossRefPubMed

64.

Gao R, Brigstock DR: Connective tissue growth factor (CCN2) induces adhesion of rat activated hepatic stellate cells by binding of its C-terminal domain to integrin alpha(v)beta(3) and heparan sulfate proteoglycan. J Biol Chem. 2004, 279: 8848-8855. 10.1074/jbc.M313204200.CrossRefPubMed

65.

Grotendorst GR: Connective tissue growth factor: a mediator of TGF-beta action on fibroblasts. Cytokine Growth Factor Rev. 1997, 8: 171-179. 10.1016/S1359-6101(97)00010-5.CrossRefPubMed

66.

Leask A, Denton CP, Abraham DJ: Insights into the molecular mechanism of sustained fibrosis: The role of connective tissue growth factor in scleroderma. J Invest Dermatol. 2004, 122: 1-6. 10.1046/j.0022-202X.2003.22133.x.CrossRefPubMed

67.

Takehara K: Hypothesis: pathogenesis of systemic sclerosis. Rheumatology. 2003, 30: 755-759.

68.

Shi-Wen X, Chen Y, Denton CP, Eastwood M, Renzoni EA, Bou-Gharios G, Pearson JD, Dashwood M, du Bois RM, Black CM, et al: Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/Akt-dependent pathway and is essential for the enhanced contractile phenotype of fibroticfibroblasts. Mol Biol Cell. 2004, 15: 2707-2719. 10.1091/mbc.E03-12-0902.PubMedCentralCrossRefPubMed

69.

Shi-wen X, Howat SL, Renzoni EA, Holmes A, Pearson JD, Dashwood MR, Bou-Gharios G, Denton CP, du Bois RM, Black CM, et al: Endothelin-1 induces expression of matrix-associated genes in lung fibroblasts through MEK/ERK. J Biol Chem. 2004, 279: 23098-23103. 10.1074/jbc.M311430200.CrossRef

70.

Shephard P, Hinz B, Smola-Hess S, Meister JJ, Krieg T, Smola H: Dissecting the roles of endothelin, TGF-beta and GM-CSF on myofibroblast differentiation by keratinocytes. Thromb Haemost. 2004, 92: 262-274.PubMed

71.

Horstmeyer A, Licht C, Scherr G, Eckes B, Krieg T: Signalling and regulation of collagen I synthesis by ET-1 and TGF-beta1. FEBS J. 2005, 272: 6297-6309. 10.1111/j.1742-4658.2005.05016.x.CrossRefPubMed

72.

Denton CP, Black CM: Pulmonary hypertension in systemic sclerosis. Rheum Dis Clin North Am. 2003, 29: 335-349. 10.1016/S0889-857X(03)00024-3. viiCrossRefPubMed

73.

Korn JH, Mayes M, Matucci Cerinic M, Rainisio M, Pope J, Hachulla E, Rich E, Carpentier P, Molitor J, Seibold JR, et al: Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum. 2004, 50: 3985-3993. 10.1002/art.20676.CrossRefPubMed

Title: Scar wars: is TGFβ the phantom menace in scleroderma?
Publication date: 01-08-2006
Published in: Arthritis Research & Therapy / Issue 4/2006
Electronic ISSN: 1478-6362
DOI: https://doi.org/10.1186/ar1976

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Scar wars: is TGFβ the phantom menace in scleroderma?

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2006

Association of FCGR2A and FCGR2A-FCGR3Ahaplotypes with susceptibility to giant cell arteritis

Expression of bioactive bone morphogenetic proteins in the subacromial bursa of patients with chronic degeneration of the rotator cuff

Erratum to: Fish oil: what the prescriber needs to know

Human, viral or mutant human IL-10 expressed after local adenovirus-mediated gene transfer are equally effective in ameliorating disease pathology in a rabbit knee model of antigen-induced arthritis

Biology and therapy of fibromyalgia. New therapies in fibromyalgia

Independent associations of anti-cyclic citrullinated peptide antibodies and rheumatoid factor with radiographic severity of rheumatoid arthritis

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page