RT Journal Article
SR Electronic
T1 Wnt-heparan sulfate proteoglycan interaction in fibrotic lung disease
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP P3904
VO 44
IS Suppl 58
A1 Sarah Vierkotten
A1 Verena Aumiller
A1 Franziska Uhl
A1 Melanie Königshoff
YR 2014
UL http://erj.ersjournals.com/content/44/Suppl_58/P3904.abstract
AB Introduction:Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of yet unknown etiology. Recently, (re)activation of developmental pathways, such as Wnt/β-catenin in the alveolar epithelium has been linked to disease development. Regulation of Wnt/β-catenin activation has been shown to be dependent on Heparan Sulfate Proteoglycans (HSPGs). The role of Wnt-HSPG interaction in IPF, however, remains to be elusive. Methods: Murine and human lung epithelial cells were treated with Heparin, Desulfated (DS) Heparins or Heparinase II and Chondroitinase ABC, respectively. A Heparin binding assay was used to assess binding of Wnt3a to Heparin and DS Heparins. Immunofluorescence staining of ex vivo lung tissue for Wnt proteins and HSPGs was conducted. Results: Immunofluorescence staining of ex vivo tissue lung slices revealed upregulated WNT3a and HSPG expression in bleomycin-treated mouse lungs compared to controls. Heparin treatment of murine lung epithelial cells resulted in inhibition of TOP/FOP-flash reporter, indicating decreased canonical WNT signaling. In contrast, Heparinase II and Chondroitinase ABC treatment resulted in upregulated β-catenin-dependent gene transcription. Interestingly, 6-O-DS Heparin treatment of A549 cells did not decrease WNT signaling, while binding of WNT3a to 6-O-DS Heparin was not altered, thereby suggesting less inhibition of WNT signaling upon binding to 6-O-DS Heparin. Conclusion: Taken together, our findings revealed that HS sulfation and degradation modulates WNT/β-catenin signal activity. Altered sulfation states during ECM remodeling in IPF pathology might contribute to (re)activation of developmental pathways like WNT/β-catenin.