Increased Levels of BAMBI Inhibit Canonical TGF-β Signaling in Chronic Wound Tissues
Sabrina Ehnert,
Helen Rinderknecht,
Chao Liu,
Melanie Voss,
Franziska M. Konrad,
Wiebke Eisler,
Dorothea Alexander,
Kristian-Christos Ngamsri,
Tina Histing,
Mika F. Rollmann,
Andreas K. Nussler
Affiliations
Sabrina Ehnert
Siegfried Weller Research Institute, BG Unfallklinik Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Schnarrenbergstr. 95, 72076 Tübingen, Germany
Helen Rinderknecht
Siegfried Weller Research Institute, BG Unfallklinik Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Schnarrenbergstr. 95, 72076 Tübingen, Germany
Chao Liu
Siegfried Weller Research Institute, BG Unfallklinik Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Schnarrenbergstr. 95, 72076 Tübingen, Germany
Melanie Voss
Siegfried Weller Research Institute, BG Unfallklinik Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Schnarrenbergstr. 95, 72076 Tübingen, Germany
Franziska M. Konrad
Department of Anesthesiology and Intensive Care Medicine, University Hospital of Tübingen, Hoppe-Seyler-Straße 3, 72076 Tübingen, Germany
Wiebke Eisler
Siegfried Weller Research Institute, BG Unfallklinik Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Schnarrenbergstr. 95, 72076 Tübingen, Germany
Dorothea Alexander
Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, Osianderstr 2-8, 72076 Tübingen, Germany
Kristian-Christos Ngamsri
Department of Anesthesiology and Intensive Care Medicine, University Hospital of Tübingen, Hoppe-Seyler-Straße 3, 72076 Tübingen, Germany
Tina Histing
Siegfried Weller Research Institute, BG Unfallklinik Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Schnarrenbergstr. 95, 72076 Tübingen, Germany
Mika F. Rollmann
Siegfried Weller Research Institute, BG Unfallklinik Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Schnarrenbergstr. 95, 72076 Tübingen, Germany
Andreas K. Nussler
Siegfried Weller Research Institute, BG Unfallklinik Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Schnarrenbergstr. 95, 72076 Tübingen, Germany
Chronic wounds affect more than 2% of the population worldwide, with a significant burden on affected individuals, healthcare systems, and societies. A key regulator of the entire wound healing cascade is transforming growth factor beta (TGF-β), which regulates not only inflammation and extracellular matrix formation but also revascularization. This present work aimed at characterizing wound tissues obtained from acute and chronic wounds regarding angiogenesis, inflammation, as well as ECM formation and degradation, to identify common disturbances in the healing process. Serum and wound tissues from 38 patients (N = 20 acute and N = 18 chronic wounds) were analyzed. The patients’ sera suggested a shift from VEGF/VEGFR to ANGPT/TIE2 signaling in the chronic wounds. However, this shift was not confirmed in the wound tissues. Instead, the chronic wound tissues showed increased levels of MMP9, a known activator of TGF-β. However, regulation of TGF-β target genes, such as CTGF, COL1A1, or IL-6, was absent in the chronic wounds. In wound tissues, all three TGF-β isoforms were expressed with increased levels of TGF-β1 and TGF-β3 and a reporter assay confirmed that the expressed TGF-β was activated. However, Western blots and immunostaining showed decreased canonical TGF-β signaling in the respective chronic wound tissues, suggesting the presence of a TGF-β inhibitor. As a potential regulatory mechanism, the TGF-β proteome profiler array suggested elevated levels of the TGF-β pseudo-receptor BAMBI. Also, tissue expression of BAMBI was significantly increased not only in chronic wounds (10.6-fold) but also in acute wounds that had become chronic (9.5-fold). In summary, our data indicate a possible regulatory role of BAMBI in the development of chronic wounds. The available few in vivo studies support our findings by postulating a therapeutic potential of BAMBI for controlling scar formation.
