Discoidin domain receptor 1 regulates bronchial epithelial repair and matrix metalloproteinase production.
Discoidin domain receptor (DDR)1 is an extracellular matrix (ECM)-sensing receptor tyrosine kinase, which is activated by collagen and expressed in bronchial epithelium. DDR1 is responsible for maintaining the normal structure of skin and kidney epithelia and we hypothesised that DDR1 plays a regulatory role in bronchial epithelial integrity by transducing signals from the airway ECM. Effects of DDR1 depletion were studied using RNA interference in primary human bronchial epithelial cells (HBECs) and BEAS-2B cells. The effects of overexpression of DDR1a and DDR1b in BEAS-2B cells were studied using a plasmid vector. We measured the effects on epithelial repair using a scratch wounding model, and levels of matrix metalloproteinases (MMPs) by gelatin zymography (MMP-2 and -9) and ELISA (MMP-7). We showed that knockdown of DDR1 slowed epithelial repair by 50%, which was associated with a reduction in levels of MMP-7, whilst DDR1 overexpression enhanced epithelial repair. DDR1 knockdown reduced proliferation of HBECs, but had no significant effect on adhesion to collagen I or other matrix substrates. These data suggest that ECM signalling via DDR1 regulates aspects of bronchial epithelial repair, integrity and MMP expression in the airways.
Roberts
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ME
Division of Therapeutics and Molecular Medicine, Respiratory Biomedical Research Unit, University of Nottingham, D Floor South Block, Queen's Medical Centre, Nottingham, NG7 2UH, UK.
Magowan
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L
Hall
I P
IP
Johnson
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SR
D000328:Adult; D000368:Aged; D001249:Asthma / Q000201:enzymology / Q000473:pathology; D001980:Bronchi / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D000070819:Discoidin Domain Receptor 1; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008875:Middle Aged; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012907:Smoking / Q000378:metabolism; D014945:Wound Healing; D055815:Young Adult
D024042:Collagen Type I; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases; D020783:Matrix Metalloproteinase 7; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9