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Transforming growth factor beta 1 regulates the expression of CCN2 in human keratinocytes via Smad-ERK signalling
Brown University, RI 02903 USA.
Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Disaster Medicine and Traumatology.
Harvard Medical Sch, MA USA.
2017 (English)In: International Wound Journal, ISSN 1742-4801, E-ISSN 1742-481X, Vol. 14, no 6, p. 1006-1018Article in journal (Refereed) Published
Abstract [en]

Connective tissue growth factor (CCN2/CTGF) and transforming growth factor 1 (TGF-1) are important regulators of skin wound healing, but controversy remains regarding their expression in epithelial cell lineages. Here, we investigate the expression of CCN2 in keratinocytes during reepithelialisation and its regulation by TGF-1. CCN2 was detected in the epidermis of healing full-thickness porcine wounds. Human keratinocytes were incubated with or without 10 ng/ml TGF-1, and signalling pathways were blocked with 10-M SIS3 or 20-M PD98059. Semi-quantitative real-time PCR was used to study CCN2 mRNA expression, and western blot was used to measure CCN2, phosphorylated-ERK1/2, ERK1/2, phosphorylated-Smad3 and Smad2/3 proteins. CCN2 was transiently expressed in neoepidermis at the leading edge of the wound in vivo. In vitro, CCN2 expression was induced by TGF-1 at 2 hours (7amp;lt;boldamp;gt;amp;lt;/boldamp;gt;5 +/- 1amp;lt;boldamp;gt;amp;lt;/boldamp;gt;9-fold mRNA increase and 3amp;lt;boldamp;gt;amp;lt;/boldamp;gt;0 +/- 0amp;lt;boldamp;gt;amp;lt;/boldamp;gt;6-fold protein increase) and 12 hours (5amp;lt;boldamp;gt;amp;lt;/boldamp;gt;4 +/- 1amp;lt;boldamp;gt;amp;lt;/boldamp;gt;9-fold mRNA increase and 3amp;lt;boldamp;gt;amp;lt;/boldamp;gt;3 +/- 0amp;lt;boldamp;gt;amp;lt;/boldamp;gt;6-fold protein increase). Compared with inhibiting the SMAD pathway, inhibiting the mitogen-activated protein kinase (MAPK) pathway was more effective in reducing TGF-1-induced CCN2 mRNA and protein expression. Inhibition of the MAPK pathway had minimal impact on the activity of the SMAD pathway. CCN2 is expressed in keratinocytes in response to tissue injury or TGF-1. In addition, TGF-1 induces CCN2 expression in keratinocytes through the ras/MEK/ERK pathway. A complete understanding of CCN2 expression in keratinocytes is critical to developing novel therapies for wound healing and cutaneous malignancy.

Place, publisher, year, edition, pages
WILEY , 2017. Vol. 14, no 6, p. 1006-1018
Keywords [en]
CCN2; Cell migration; Keratinocytes; Reepithelialisation; Wound healing
National Category
Microbiology in the medical area
Identifiers
URN: urn:nbn:se:liu:diva-143930DOI: 10.1111/iwj.12749ISI: 000416424400019PubMedID: 28371159OAI: oai:DiVA.org:liu-143930DiVA, id: diva2:1169786
Available from: 2017-12-29 Created: 2017-12-29 Last updated: 2018-05-02

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Junker, Johan
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Division of Surgery, Orthopedics and OncologyFaculty of Medicine and Health SciencesCenter for Disaster Medicine and Traumatology
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