Abstract
Transforming growth factor beta (TGFbeta) is important in inflammation, angiogenesis, reepithelialization and connective tissue regeneration during wound healing. We analyzed components of TGFbeta signaling pathway in biopsies from 10 patients with nonhealing venous ulcers (VUs). Using comparative genomics of transcriptional profiles of VUs and TGFbeta-treated keratinocytes, we found deregulation of TGFbeta target genes in VUs. Using quantitative polymerase chain reaction (qPCR) and immunohistochemical analysis, we found suppression of TGFbeta RI, TGFbeta RII and TGFbeta RIII, and complete absence of phosphorylated Smad2 (pSmad2) in VU epidermis. In contrast, pSmad2 was induced in the cells of the migrating epithelial tongue of acute wounds. TGFbeta-inducible transcription factors (GADD45beta , ATF3 and ZFP36L1) were suppressed in VUs. Likewise, genes suppressed by TGFbeta (FABP5, CSTA and S100A8) were induced in nonhealing VUs. An inhibitor of Smad signaling, Smad7 was also downregulated in VUs. We conclude that TGFbeta signaling is functionally blocked in VUs by downregulation of TGFbeta receptors and attenuation of Smad signaling resulting in deregulation of TGFbeta target genes and consequent hyperproliferation. These data suggest that application of exogenous TGFbeta may not be a beneficial treatment for VUs.
Highlights
Chronic wounds, including venous ulcers, represent a challenging clinical problem
Transforming growth factor β (TGFβ) Signaling Is Reduced in venous ulcers (VUs) To analyze TGFβ signaling in the epidermis of the wound edge of VUs, we compared transcriptional profiles of biopsies obtained from VU patients [2] with profiles of primary human keratinocytes treated with TGFβ (Blumenberg M and Zavadil J, unpublished data) using the LOLA program [32,40,42]
RNA isolated from VU biopsies predominantly originated from hyperproliferative epidermal keratinocytes, and the amount of dermal RNA was minimal according to expression of the mesenchymal tissue marker vimentin1
Summary
Chronic wounds, including venous ulcers, represent a challenging clinical problem. In the US, each year more than 8 million patients develop chronic nonhealing wounds, including pressure, venous and diabetic ulcers and burns [1]. Transforming growth factor β (TGFβ) is a pleiotropic cytokine that participates in maintenance of epidermal homeostasis. It is known as growthinhibitory cytokine, in epithelial tissues [7]. TGFβ coordinates the wound-healing response [8] and regulates reepithelialization, inflammation, granulation-tissue formation and wound contraction [6,9,10,11]. TGFβ mediates its signaling by binding to TGFβ receptor II (TGFβRII) followed by heterodimerization and phosphorylation of TGFβ receptor I (TGFβRI) [12,13]
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