Attenuation of the transforming growth factor β-signaling pathway in chronic venous ulcers

Irena Pastar, Olivera Stojadinovic, Agata Krzyzanowska, Stephan Barrientos, Christina Stuelten, Karen Zimmerman, Miroslav Blumenberg, Harold Brem, Marjana Tomic-Canic

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Transforming growth factor β (TGFβ) is important in inflammation, angiogenesis, reepithelialization and connective tissue regeneration during wound healing. We analyzed components of TGFβ signaling pathway in biopsies from 10 patients with nonhealing venous ulcers (VUs). Using comparative genomics of transcriptional profiles of VUs and TGFβ-treated keratinocytes, we found deregulation of TGFβ target genes in VUs. Using quantitative polymerase chain reaction (qPCR) and immunohistochemical analysis, we found suppression of TGFβRI, TGFβRII and TGFβRIII, 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. TGFβ-inducible transcription factors ( GADD45β, ATF3 and ZFP36L1) were suppressed in VUs. Likewise, genes suppressed by TGFβ ( FABP5, CSTA and S100A8) were induced in nonhealing VUs. An inhibitor of Smad signaling, Smad7 was also downregulated in VUs. We conclude that TGFβ signaling is functionally blocked in VUs by downregulation of TGFβ receptors and attenuation of Smad signaling resulting in deregulation of TGFβ target genes and consequent hyperproliferation. These data suggest that application of exogenous TGFβ may not be a beneficial treatment for VUs.

Original languageEnglish
Pages (from-to)92-101
Number of pages10
JournalMolecular Medicine
Volume16
Issue number3-4
DOIs
StatePublished - Mar 1 2010

Fingerprint

Varicose Ulcer
Transforming Growth Factors
Activating Transcription Factor 3
Down-Regulation
Genes
Growth Factor Receptors
Genomics
Keratinocytes
Tongue
Epidermis
Connective Tissue
Wound Healing
Regeneration
Epithelial Cells
Inflammation
Biopsy

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

Cite this

Attenuation of the transforming growth factor β-signaling pathway in chronic venous ulcers. / Pastar, Irena; Stojadinovic, Olivera; Krzyzanowska, Agata; Barrientos, Stephan; Stuelten, Christina; Zimmerman, Karen; Blumenberg, Miroslav; Brem, Harold; Tomic-Canic, Marjana.

In: Molecular Medicine, Vol. 16, No. 3-4, 01.03.2010, p. 92-101.

Research output: Contribution to journalArticle

Pastar, I, Stojadinovic, O, Krzyzanowska, A, Barrientos, S, Stuelten, C, Zimmerman, K, Blumenberg, M, Brem, H & Tomic-Canic, M 2010, 'Attenuation of the transforming growth factor β-signaling pathway in chronic venous ulcers', Molecular Medicine, vol. 16, no. 3-4, pp. 92-101. https://doi.org/10.2119/molmed.2009.00149
Pastar I, Stojadinovic O, Krzyzanowska A, Barrientos S, Stuelten C, Zimmerman K et al. Attenuation of the transforming growth factor β-signaling pathway in chronic venous ulcers. Molecular Medicine. 2010 Mar 1;16(3-4):92-101. https://doi.org/10.2119/molmed.2009.00149
Pastar, Irena ; Stojadinovic, Olivera ; Krzyzanowska, Agata ; Barrientos, Stephan ; Stuelten, Christina ; Zimmerman, Karen ; Blumenberg, Miroslav ; Brem, Harold ; Tomic-Canic, Marjana. / Attenuation of the transforming growth factor β-signaling pathway in chronic venous ulcers. In: Molecular Medicine. 2010 ; Vol. 16, No. 3-4. pp. 92-101.
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