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Inhibition of bone morphogenetic protein signalling promotes wound healing in a human ex vivo model

  • Experimental Study
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Abstract

Background

Bone morphogenetic proteins (BMPs) and their receptors (BMPRs) play roles in embryonic development and postnatal remodelling of the skin. Many indications suggest that BMP signalling regulates keratinocyte proliferation and differentiation. Chronic wounds have been shown to exhibit high levels of BMP ligands; however, the effect of BMP pathway modulation on human skin healing remains undefined.

Methods

A human ex vivo skin wound healing model was used to analyse the expression of BMP signalling pathway components during healing and to investigate the effects of BMPs and the BMP antagonist Noggin on skin repair. Additionally, the effects of BMP signalling on keratinocyte proliferation, apoptosis and migration were tested using in vitro flow cytometry and ‘scratch’ migration assays, respectively.

Results

BMP receptor-1B (BMPR-1B) and downstream signalling protein phosphorylated-Smad-1/5/8 were highly expressed in healing epidermis. Treatment of human skin with exogenous BMPs impaired wound closure by reducing keratinocyte proliferation and increasing apoptosis. The BMP antagonist Noggin negated the inhibitory effects of BMP ligands, and when used alone, Noggin reduced keratinocyte apoptosis in the wound bed. In vitro, BMP ligands suppressed keratinocyte proliferation whilst Noggin stimulated proliferation. Keratinocyte migration was slowed following BMP treatment; in contrast, migration was significantly accelerated due to inhibition of BMP activity by either Noggin or BMPR-1B silencing.

Conclusions

BMP signalling is inherently involved in wound healing. BMPs slow skin repair by suppressing keratinocyte proliferation and migration. Thus, modulation of BMP signalling using BMP inhibitors such as Noggin may serve as a new approach to promote cutaneous wound repair.

Level of evidence: Not ratable.

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Ethical declaration

This work conforms to the ethical standards set out in the Declaration of Helsinki and was approved by the local research ethics committee. All patients were provided with informed consent and provided written consent for the use of their discarded tissue.

Conflicts of interest

None.

Patient consent

Patients provided written consent for the use of their images.

Funding sources

This research is funded by the University of Bradford Plastic Surgery & Burns Unit Charity Fund.

Author information

Authors and Affiliations

  1. Plastic Surgery & Burns Research Unit, University of Bradford, West Yorkshire, UK

    Christopher John Lewis & David Sharpe

  2. Centre for Skin Sciences, Richmond Building, University of Bradford, West Yorkshire, BD7 1DP, UK

    Andrei Mardaryev & Natalia Botchkareva

Authors
  1. Christopher John Lewis
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  2. Andrei Mardaryev
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  3. David Sharpe
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  4. Natalia Botchkareva
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Corresponding author

Correspondence to Natalia Botchkareva.

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Lewis, C.J., Mardaryev, A., Sharpe, D. et al. Inhibition of bone morphogenetic protein signalling promotes wound healing in a human ex vivo model. Eur J Plast Surg 38, 1–12 (2015). https://doi.org/10.1007/s00238-014-1031-8

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  • DOI: https://doi.org/10.1007/s00238-014-1031-8

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