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Archives of Dermatological Research

, Volume 310, Issue 8, pp 615–623 | Cite as

LY2109761 reduces TGF-β1-induced collagen production and contraction in hypertrophic scar fibroblasts

  • Guo Wei
  • Qingqing Xu
  • Lin Liu
  • Huanhuan Zhang
  • Xi Tan
  • Chunhong Zhang
  • Changyu Han
  • Yanxia Guo
  • Ganwen Han
  • Chunmin Zhang
Original Paper
  • 141 Downloads

Abstract

Hypertrophic scars (HS) are fibro-hyperproliferative dermal lesions with effusive continuous accumulation of extracellular matrix components, particularly collagen. They usually occur after dermal injury in genetically susceptible individuals and cause both physical and psychological distress for the affected individuals. Transforming growth factor-β1 (TGF-β1) is known to mediate wound healing process by regulating cell differentiation, collagen production and extracellular matrix degradation. The sustained high expression of TGF-β1 is believed to result in the formation of hypertrophic scars. Inhibition of TGF-β1 signaling pathway may represent one of effective strategies for limiting excessive scarring. LY2109761, an orally active TβRI/II kinase dual inhibitor, has been previously reported that it had inhibitory effects on carcinomas and attenuates Radiation-induced pulmonary murine fibrosis. Our results revealed that LY2109761 reduced TGF-β1-induced collagen production and α-smooth muscle actin (α-SMA) expression, and attenuated TGF-β1-induced cell contraction in hypertrophic scar fibroblasts. The data from this study provide evidence supporting the potential use of LY2109761 as a novel treatment for hypertrophic scars.

Keywords

Hypertrophic scars Transforming growth factor beta LY2109761 Collagen α-Smooth muscle actin 

Notes

Acknowledgements

We would like to thank Professor Huiqing Yuan for kindly providing technical support. This work was supported by the Shandong Natural Science Foundation (No. ZR2014HM030, No. ZR2014HL046), the National Natural Science Foundation of China (No. 81472903) and Jinan science and technology plan projects (201503019).

Compliance with ethical standards

Conflict of interest

None of the authors has any financial or other interest with regard to the submitted manuscript that might be constructed as a conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

403_2018_1849_MOESM1_ESM.docx (250 kb)
Supplementary material 1 (DOCX 250 KB)

References

  1. 1.
    Bock O, Schmid-Ott G, Malewski P et al (2006) Quality of life of patients with keloid and hypertrophic scarring. Arch Dermatol Res 297(10):433–438CrossRefPubMedGoogle Scholar
  2. 2.
    Border WA, Noble NA (1994) Transforming growth factor beta in tissue fibrosis. N Engl J Med 331(19):1286–1292CrossRefPubMedGoogle Scholar
  3. 3.
    Branton MH, Kopp JB (1999) TGF-beta and fibrosis. Microbes Infect 1(15):1349–1365CrossRefPubMedGoogle Scholar
  4. 4.
    Chin GS, Liu W, Peled Z et al (2001) Differential expression of transforming growth factor-beta receptors I and II and activation of Smad 3 in keloid fibroblasts. Plast Reconstr Surg 108(2):423–429CrossRefPubMedGoogle Scholar
  5. 5.
    Connolly EC, Saunier EF, Quigley D et al (2011) Outgrowth of drug-resistant carcinomas expressing markers of tumor aggression after long-term TbetaRI/II kinase inhibition with LY2109761. Cancer Res 71(6):2339–2349CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Flechsig P, Dadrich M, Bickelhaupt S et al (2012) LY2109761 attenuates radiation-induced pulmonary murine fibrosis via reversal of TGF-beta and BMP-associated proinflammatory and proangiogenic signals. Clin Cancer Res 18(13):3616–3627CrossRefPubMedGoogle Scholar
  7. 7.
    Fransvea E, Angelotti U, Antonaci S et al (2008) Blocking transforming growth factor-beta up-regulates E-cadherin and reduces migration and invasion of hepatocellular carcinoma cells. Hepatology 47(5):1557–1566CrossRefPubMedGoogle Scholar
  8. 8.
    Franz M, Spiegel K, Umbreit C et al (2009) Expression of Snail is associated with myofibroblast phenotype development in oral squamous cell carcinoma. Histochem Cell Biol 131(5):651–660CrossRefPubMedGoogle Scholar
  9. 9.
    Gao Y, Shan N, Zhao C et al (2015) LY2109761 enhances cisplatin antitumor activity in ovarian cancer cells. Int J Clin Exp Pathol 8(5):4923–4932PubMedPubMedCentralGoogle Scholar
  10. 10.
    Gauglitz GG, Korting HC, Pavicic T et al (2011) Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies. Mol Med 17(1–2):113–125PubMedGoogle Scholar
  11. 11.
    He S, Liu X, Yang Y et al (2010) Mechanisms of transforming growth factor β1/Smad signalling mediated by mitogen-activated protein kinase pathways in keloid fibroblasts. Br J Dermatol 162(3):538–546CrossRefPubMedGoogle Scholar
  12. 12.
    Henderson J, Ferguson MW, Terenghi G (2012) The reinnervation pattern of wounds and scars after treatment with transforming growth factor beta isoforms. J Plast Reconstr Aesthet Surg 65(4):e80–e86CrossRefPubMedGoogle Scholar
  13. 13.
    Huang D, Shen KH, Wang HG (2013) Pressure therapy upregulates matrix metalloproteinase expression and downregulates collagen expression in hypertrophic scar tissue. Chin Med J (Engl) 126(17):3321–3324Google Scholar
  14. 14.
    Jagadeesan J, Bayat A (2007) Transforming growth factor beta (TGFbeta) and keloid disease. Int J Surg 5(4):278–285CrossRefPubMedGoogle Scholar
  15. 15.
    Melisi D, Ishiyama S, Sclabas GM et al (2008) LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol Cancer Ther 7(4):829–840CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Phan TT, Lim IJ, Chan SY et al (2004) Suppression of transforming growth factor beta/Smad signaling in keloid-derived fibroblasts by quercetin: implications for the treatment of excessive scars. J Trauma 57(5):1032–1037CrossRefPubMedGoogle Scholar
  17. 17.
    Ren XF, Mu LP, Jiang YS et al (2015) LY2109761 inhibits metastasis and enhances chemosensitivity in osteosarcoma MG-63 cells. Eur Rev Med Pharmacol Sci 19(7):1182–1190PubMedGoogle Scholar
  18. 18.
    Tang LX, He RH, Yang G et al (2012) Asiatic acid inhibits liver fibrosis by blocking TGF-beta/Smad signaling in vivo and in vitro. PLoS One 7(2):e31350CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Varga J, Abraham D (2007) Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest 117(3):557–567CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Wang J, Dodd C, Shankowsky HA et al (2008) Deep dermal fibroblasts contribute to hypertrophic scarring. Lab Invest 88(12):1278–1290CrossRefPubMedGoogle Scholar
  21. 21.
    Wang Z, Gao Z, Shi Y et al (2007) Inhibition of Smad3 expression decreases collagen synthesis in keloid disease fibroblasts. J Plast Reconstr Aesthet Surg 60(11):1193–1199CrossRefPubMedGoogle Scholar
  22. 22.
    Wells A, Nuschke A, Yates CC (2016) Skin tissue repair: matrix microenvironmental influences. Matrix Biol 49:25–36CrossRefPubMedGoogle Scholar
  23. 23.
    Wendt MK, Tian M, Schiemann WP (2012) Deconstructing the mechanisms and consequences of TGF-beta-induced EMT during cancer progression. Cell Tissue Res 347(1):85–101CrossRefPubMedGoogle Scholar
  24. 24.
    Wrana JL, Attisano L (2000) The Smad pathway. Cytokine Growth Factor Rev 11(1–2):5–13CrossRefPubMedGoogle Scholar
  25. 25.
    Xu Y, Tabe Y, Jin L et al (2008) TGF-beta receptor kinase inhibitor LY2109761 reverses the anti-apoptotic effects of TGF-beta1 in myelo-monocytic leukaemic cells co-cultured with stromal cells. Br J Haematol 142(2):192–201CrossRefPubMedGoogle Scholar
  26. 26.
    Zhang B, Halder SK, Zhang S et al (2009) Targeting transforming growth factor-beta signaling in liver metastasis of colon cancer. Cancer Lett 277(1):114–120CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Zhang C, Xu Q, Tan X et al (2017) Astilbin decreases proliferation and improves differentiation in HaCaT keratinocytes. Biomed Pharmacother 93:713–720CrossRefPubMedGoogle Scholar
  28. 28.
    Zhang M, Kleber S, Rohrich M et al (2011) Blockade of TGF-beta signaling by the TGFbetaR-I kinase inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma. Cancer Res 71(23):7155–7167CrossRefPubMedGoogle Scholar
  29. 29.
    Zhang Z, Garron TM, Li XJ et al (2009) Recombinant human decorin inhibits TGF-beta1-induced contraction of collagen lattice by hypertrophic scar fibroblasts. Burns 35(4):527–537CrossRefPubMedGoogle Scholar
  30. 30.
    Zhao D, Wang Y, Du C et al (2017) Honokiol alleviates hypertrophic scar by targeting transforming growth factor-beta/Smad2/3 signaling pathway. Front Pharmacol 8:206PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Guo Wei
    • 1
  • Qingqing Xu
    • 1
  • Lin Liu
    • 1
  • Huanhuan Zhang
    • 1
  • Xi Tan
    • 1
  • Chunhong Zhang
    • 1
  • Changyu Han
    • 1
  • Yanxia Guo
    • 2
  • Ganwen Han
    • 1
    • 3
  • Chunmin Zhang
    • 1
  1. 1.Department of Dermato-venereologythe Second Hospital of Shandong UniversityJinanChina
  2. 2.Institute of Medical Sciencesthe Second Hospital of Shandong UniversityJinanChina
  3. 3.Department of DermatologyPeking University International HospitalBeijingChina

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