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Botulinum toxin type A suppresses pro-fibrotic effects via the JNK signaling pathway in hypertrophic scar fibroblasts

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Abstract

Hypertrophic scar is a dermal fibroproliferative disease characterized by the overproduction and deposition of extracellular matrix, and the hyperproliferation and enhanced angiogenesis of fibroblasts, along with their enhanced differentiation to myofibroblasts. Botulinum toxin type A shows potential for prevention of hypertrophic scar formation; however, its effectiveness in attenuating skin fibrosis and the related mechanism are unclear. In this study, human scar fibroblasts were cultured and stimulated with botulinum toxin type A, and the changes in fibroblast proliferation, migration, and protein expression of pro-fibrotic factors were evaluated with colorimetric, scratch, and enzyme-linked immunosorbent assays and western blotting, respectively. Botulinum toxin type A treatment decreased the proliferation and migration of human scar fibroblasts compared with those of untreated controls. Protein expression levels of pro-fibrotic factors (transforming growth factor β1, interleukin-6, and connective tissue growth factor) were also inhibited by botulinum toxin type A, whereas the JNK phosphorylation level was increased. Activation of the JNK pathway demonstrated the inhibitory effects of the toxin on human scar fibroblast proliferation and production of pro-fibrotic factors, suggesting that the suppressive effects of botulinum toxin type A are closely associated with JNK phosphorylation. Overall, this study showed that botulinum toxin type A has a suppressive effect on extracellular matrix production and scar-related factors in human scar fibroblasts in vitro, and that regulation of JNK signaling plays an important role in this process. Our results provide a theoretical basis, at the cellular level, for the therapeutic use of botulinum toxin type A.

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Funding

This research was supported by AmorePacific Grant in 2015.

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Author notes

  1. Gil Soon Park and Min Kyun An contributed equally to this work.

Authors and Affiliations

  1. Department of Dermatology, Hallym Institute for Translational Medicine, Anyang, South Korea

    Gil Soon Park

  2. Department of Dermatology, Hallym University Sacred Heart Hospital, 22 Gwanpyeong-ro 170 Beon-gil, Dongan-gu, Anyang, Gyeonggi-do, 14068, South Korea

    Min Kyun An, Ji Ha Yoon, Eun Byul Cho, Eun Joo Park, Kwang Ho Kim & Kwang Joong Kim

  3. Department of Convergence Medicine, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, South Korea

    Seok Soon Park

  4. Department of Plastic Surgery, Gwangmyeong Sungae Hospital, Gwangmyeong, South Korea

    Sung Hoon Koh

  5. Department of Dermatology, VA Medical Center, University of California, San Francisco, CA, USA

    Theodora M. Mauro

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  1. Gil Soon Park
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Correspondence to Eun Joo Park.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Park, G.S., An, M.K., Yoon, J.H. et al. Botulinum toxin type A suppresses pro-fibrotic effects via the JNK signaling pathway in hypertrophic scar fibroblasts. Arch Dermatol Res 311, 807–814 (2019). https://doi.org/10.1007/s00403-019-01975-0

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  • DOI: https://doi.org/10.1007/s00403-019-01975-0

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