Attenuation of the Transforming Growth Factor β-Signaling Pathway in Chronic Venous Ulcers

Transforming growth factor beta (TGF beta) is important in inflammation, angiogenesis, reepithelialization and connective tissue regeneration during wound healing. We analyzed components of TGF beta signaling pathway in biopsies from 10 patients with nonhealing venous ulcers (VUs). Using comparative genomics of transcriptional profiles of VUs and TGF beta-treated keratinocytes, we found deregulation of TGF beta target genes in VUs. Using quantitative polymerase chain reaction (qPCR) and immunohistochemical analysis, we found suppression of TGF beta RI, TGWU and TGF beta 3RIII, 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. TGF beta-inducible transcription factors (GADD45 beta, ATF3 and ZFP36L1) were suppressed in VUs. Likewise, genes suppressed by TGF beta (FABP5, CSTA and S100A8) were induced in nonhealing VUs. An inhibitor of Smad signaling, Smad7 was also downregulated in VUs. We conclude that TGF beta signaling is functionally blocked in VUs by downregulation of TGF beta receptors and attenuation of Smad signaling resulting in deregulation of TGF beta target genes and consequent hyperproliferation. These data suggest that application of exogenous TGF beta may not be a beneficial treatment for VUs. (C) 2010 The Feinstein Institute for Medical Research, www.feinsteininstitute.org Online address: http://www.molmed.org doi: 10.2119/molmed.2009.00149