Halofuginone down-regulates Smad3 expression and inhibits the TGFbeta-induced expression of fibrotic markers in human corneal fibroblasts

Molecular Vision

Volumn 18, Issue , 2012, Pages 479-487

  Nelson, Elizabeth F ^a   Huang, Craig W ^a   Ewel, Jillian M ^a   Chang, Angela A ^a   Yuan, Ching ^a  

^a UNIVERSITY OF MINNESOTA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA SMOOTH MUSCLE ACTIN; BIOLOGICAL MARKER; COLLAGEN TYPE 1; FIBRONECTIN; HALOFUGINONE; MESSENGER RNA; PHALLOIDIN; SMAD2 PROTEIN; SMAD3 PROTEIN; TRANSFORMING GROWTH FACTOR BETA;

ARTICLE; CELL VIABILITY; CONCENTRATION RESPONSE; CONTROLLED STUDY; CORNEA; CORNEAL FIBROBLAST; CORNEAL FIBROSIS; CYTOTOXICITY; DOWN REGULATION; DRUG ACTIVITY; FIBROBLAST; FIBROSIS; HISTOPATHOLOGY; HUMAN; HUMAN TISSUE; IMMUNOHISTOCHEMISTRY; IN VITRO STUDY; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; QUANTITATIVE ANALYSIS; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SIGNAL TRANSDUCTION; STAINING; STRESS FIBER; TISSUE CULTURE; WESTERN BLOTTING;

ACTINS; BIOLOGICAL MARKERS; CELL SURVIVAL; CELLS, CULTURED; COLLAGEN TYPE I; CORNEA; DOSE-RESPONSE RELATIONSHIP, DRUG; FIBROBLASTS; FIBRONECTINS; FIBROSIS; GENE EXPRESSION REGULATION; HUMANS; PIPERIDINES; PROTEIN SYNTHESIS INHIBITORS; QUINAZOLINONES; SIGNAL TRANSDUCTION; SMAD3 PROTEIN; TRANSFORMING GROWTH FACTOR BETA1;

EID: 84863232768     PISSN: None     EISSN: 10900535     Source Type: Journal    
DOI: None     Document Type: Article

References (35)

1. Border WA, Noble NA. Transforming growth factor beta in tissue fibrosis. N Engl J Med 1994; 331:1286-92. [PMID: 7935686].
2. 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; 1:260-6. [PMID: 10559937].
3. Denton CP, Zheng B, Evans LA, Shi-wen X, Ong VH, Fisher I, Lazaridis K, Abraham DJ, Black CM, de Crombrugghe B. Fibroblast-specific expression of a kinase-deficient type II transforming growth factor beta (TGFbeta) receptor leads to paradoxical activation of TGFbeta signaling pathways with fibrosis in transgenic mice. J Biol Chem 2003; 278:25109-19. [PMID: 12707256].
4. Shi Y, Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003; 113:685-700. [PMID: 12809600].
5. Massagué J, Gomis RR. The logic of TGFbeta signaling. FEBS Lett 2006; 580:2811-20. [PMID: 16678165].
6. Hoodless PA, Wrana JL. Mechanism and function of signaling by the TGF beta superfamily. Curr Top Microbiol Immunol 1998; 228:235-72. [PMID: 9401209].
7. Massagué J, Seoane J, Wotton D. Smad transcription factors. Genes Dev 2005; 19:2783-810. [PMID: 16322555].
8. Saika S, Yamanaka O, Sumioka T, Miyamoto T, Miyazaki K, Okada Y, Kitano A, Shirai K, Tanaka S, Ikeda K. Fibrotic disorders in the eye: targets of gene therapy. Prog Retin Eye Res 2008; 27:177-96. [PMID: 18243038].
9. Sumioka T, Ikeda K, Okada Y, Yamanaka O, Kitano A, Saika S. Inhibitory effect of blocking TGF-β/Smad signal on injuryinduced fibrosis of corneal endothelium. Mol Vis 2008; 14:2272-81. [PMID: 19081766].
10. Sharma A, Mehan MM, Sinha S, Cowden JW, Mohan RR. Trichostatin a inhibits corneal haze in vitro and in vivo. Invest Ophthalmol Vis Sci 2009; 50:2695-701. [PMID: 19168895].
11. Chen J, Guerriero E, Sado Y, SundarRaj N. Rho-mediated regulation of TGF-beta1- and FGF-2-induced activation of corneal stromal keratocytes. Invest Ophthalmol Vis Sci 2009; 50:3662-70. [PMID: 19324862].
12. Pan H, Chen J, Xu J, Chen M, Ma R. Antifibrotic effect by activation of peroxisome proliferator-activated receptorgamma in corneal fibroblasts. Mol Vis 2009; 15:2279-86. [PMID: 19936025].
13. Granot I, Bartov I, Plavnik I, Wax E, Hurwitz S, Pines M. Increased skin tearing in broilers and reduced collagen synthesis in skin in vivo and in vitro in response to the coccidiostat halofuginone. Poult Sci 1991; 70:1559-63. [PMID: 1886867].
14. Granot I, Halevy O, Hurwitz S, Pines M. Halofuginone: an inhibitor of collagen type I synthesis. Biochim Biophys Acta 1993; 1156:107-12. [PMID: 8427869].
15. Choi ET, Callow AD, Sehgal NL, Brown DM, Ryan US. Halofuginone, a specific collagen type I inhibitor, reduces anastomotic intimal hyperplasia. Arch Surg 1995; 130:257-61. [PMID: 7887792].
16. Bocchieri MH, Jimenez SA. Animal models of fibrosis. Rheum Dis Clin North Am 1990; 16:153-67. [PMID: 2406805].
17. Zhang Y, Gilliam AC. Animal models for scleroderma: an update. Curr Rheumatol Rep 2002; 4:150-62. [PMID: 11890881].
18. McGaha TL, Kodera T, Spiera H, Stan AC, Pines M, Bona CA. Halofuginone inhibition of COL1A2 promoter activity via a c-Jun-dependent mechanism. Arthritis Rheum 2002; 46:2748-61. [PMID: 12384935].
19. Sheffer Y, Leon O, Pinthus JH, Nagler A, Mor Y, Genin O, Iluz M, Kawada N, Yoshizato K, Pines M. Inhibition of fibroblast to myofibroblast transition by halofuginone contributes to the chemotherapy-mediated antitumoral effect. Mol Cancer Ther 2007; 6:570-7. [PMID: 17267660].
20. Pines M, Domb A, Ohana M, Inbar J, Genina O, Alexiev R, Nagler A. Reduction in dermal fibrosis in the tight-skin (Tsk)mouse after local application of halofuginone. Biochem Pharmacol 2001; 62:1221-7. [PMID: 11705455].
21. Levi-Schaffer F, Nagler A, Slavin S, Knopov V, Pines M. Inhibition of collagen synthesis and changes in skin morphology in murine graft-versus-host disease and tight skin mice: effect of halofuginone. J Invest Dermatol 1996; 106:84-8. [PMID: 8592087].
22. Xavier S, Piek E, Fujii M, Javelaud D, Mauviel A, Flanders KC, Samuni AM, Felici A, Reiss M, Yarkoni S, Sowers A, Mitchell JB, Roberts AB, Russo A. Amelioration of radiationinduced fibrosis: inhibition of transforming growth factorbeta signaling by halofuginone. J Biol Chem 2004; 279:15167-76. [PMID: 14732719].
23. Pei Y, Sherry DM, McDermott AM. Thy-1 distinguishes human corneal fibroblasts and myofibroblasts from keratocytes. Exp Eye Res 2004; 79:705-12. [PMID: 15500828].
24. Taylor SE, Vaughan-Thomas A, Clements DN, Pinchbeck G, Macrory LC, Smith RKW, Clegg PD. Gene expression markers of tendon fibroblasts in normal and diseased tissue compared to monolayer and three dimensional culture systems. BMC Musculoskelet Disord 2009; 10:27. [PMID: 19245707].
25. Skovbjerg H, Anthonsen D, Lothe IM, Tveit KM, Kure EH, Vogel LK. Collagen mRNA levels changes during colorectal cancer carcinogenesis. BMC Cancer 2009; 9:136. [PMID: 19422682].
26. Wrana JL, Attisano L, Carcamo J, Zentella A, Doody J, Laiho M, Wang XF, Massague J. TGF beta signals through a heteromeric protein kiase receptor complex. Cell 1992; 71:1003-14. [PMID: 1333888].
27. Flanders KC. Smad3 as a mediator of the fibrotic response. Int J Exp Pathol 2004; 85:47-64. [PMID: 15154911].
28. Turgeman T, Hagai Y, Huebner K, Jassal DS, Anderson JE, Genin O, Nagler A, Halevy O, Pines M. Prevention of muscle fibrosis and improvement in muscle performance in the mdx mouse by halofuginone. Neuromuscul Disord 2008; 18:857-68. [PMID: 18672370].
29. Roffe S, Hagai Y, Pines M, Halevy O. Halofuginone inhibits Smad3 phosphorylation via the PI3K/Akt and MAPK/ERK pathways in muscle cells: effect on myotube fusion. Exp Cell Res 2010; 316:1061-9. [PMID: 20060825].
30. de Figueiredo-Pontes LL, Assis PA, Santana-Lemos BA, Jácomo RH, Lima AS, Garcia AB, Thomé CH, Araújo AG, Panepucci RA, Zago MA, Nagler A, Falcão RP, Rego EM. Halofuginone has anti-proliferative effects in acute promyelocytic leukemia by modulating the transforming growth factor Beta signaling pathway. PLoS ONE 2011; 6:e26713. [PMID: 22053203].
31. Kelley TJ, Elmer HL, Corey DA. Reduced Smad3 protein expression and altered transforming growth factor-beta1-mediated signaling in cystic fibrosis epithelial cells. Am J Respir Cell Mol Biol 2001; 25:732-8. [PMID: 11726399].
32. Flanders KC, Major CD, Arabshahi A, Aburime EE, Okada MH, Fujii M, Blalock TD, Schultz GS, Sowers A, Anzano MA, Mitchell JB, Russo A, Roberts AB. Interference with transforming growth factor-beta/ Smad3 signaling results in accelerated healing of wounds in previously irradiated skin. Am J Pathol 2003; 163:2247-57. [PMID: 14633599].
33. Stramer BM, Austin JS, Roberts AB, Fini ME. Selective reduction of fibrotic markers in repairing corneas of mice deficient in Smad3. J Cell Physiol 2005; 203:226-32. [PMID: 15521071].
34. Leiba M, Cahalon L, Shimoni A, Lider O, Zanin-Zhorov A, Hecht I, Sela U, Vlodavsky I, Nagler A. Halofuginone inhibits NF-kappaB and p38 MAPK in activated T cells. J Leukoc Biol 2006; 80:399-406. [PMID: 16769768].
35. Popov Y, Patsenker E, Bauer M, Niedobitek E, Schulze-Krebs A, Schuppan D. Halofuginone induces matrix metalloproteinases in rat hepatic stellate cells via activation of p38 and NFkappaB. J Biol Chem 2006; 281:15090-8. [PMID: 16489207].