Fibroblasts from chronic wounds show altered TGF-beta-signaling and decreased TGF-beta Type II receptor expression.
Chronic wounds are characterized by failure to heal in a defined time frame. However, the pathogenic steps leading from the etiological factors to failure to heal are unknown. Recently, increasing evidence suggests that resident cells in chronic wounds display a number of critical abnormalities, including senescence and unresponsiveness to the stimulatory action of transforming growth factor-beta1 (TGF-beta1). In this study, we have determined some of the mechanisms that might be responsible for unresponsiveness to TGF-beta1. Using Northern analysis and affinity labeling, we show that venous ulcer fibroblasts have decreased TGF-beta Type II receptor expression. This finding is not the result of genetic mutation, as shown by experiments with Type II receptor satellite instability. Decreased Type II receptor expression was accompanied by failure of ulcer fibroblasts to phosphorylate Smad 2, Smad 3, and p42/44 mitogen activating protein kinase (MAPK), and was associated with a slower proliferative rate in response to TGF-beta1. We conclude that venous ulcer fibroblasts show decreased Type II receptor expression and display abnormalities in the downstream signaling pathway involving MAPK and the early Smad pathway. These findings suggest ways to address and treat the abnormal cellular phenotype of cells in chronic wounds.
Kim
Byung-Chul
BC
National Institutes of Health, National Cancer Institute, Laboratory of Cell Regulation and Carcinogenesis, Bethesda, Maryland 20892, USA.
Kim
Heung Tae
HT
Park
Seok Hee
SH
Cha
Ji-Sun
JS
Yufit
Tatyana
T
Kim
Seong-Jin
SJ
Falanga
Vincent
V
D002478:Cells, Cultured; D002908:Chronic Disease; D015536:Down-Regulation; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D014647:Varicose Ulcer / Q000235:genetics / Q000378:metabolism*
D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II