Increased Levels of BAMBI Inhibit Canonical TGF-β Signaling in Chronic Wound Tissues

Abstract

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.