Bone morphogenetic protein 4 expressed in esophagitis induces a columnar phenotype in esophageal squamous cells.
OBJECTIVE
Barrett's esophagus (BE) is a metaplastic condition in which normal squamous esophageal epithelium is replaced by columnar epithelium. It is proposed that one of the possible mechanisms is dedifferentiation of squamous epithelium into columnar epithelium. The pathophysiology through which this metaplasia occurs is unknown. A recent study by serial analysis of gene expression showed that bone morphogenetic protein 4 (BMP-4) is uniquely expressed in BE. In this study, the role of the BMP pathway in the metaplastic transformation of normal squamous cells into columnar cells was examined.


METHODS
Tissues from patients with esophagitis and BE and in an esophagitis-BE rat model were examined for the activation of the BMP pathway. Short-term cultures of primary normal squamous esophageal cells were treated with BMP-4, and cell biological changes were examined by Western blot analysis, immunohistochemistry, and microarrays.


RESULTS
In both human and rat tissues, the BMP pathway proved to be activated in esophagitis and BE. Upon incubation of squamous cell cultures with BMP-4, the cytokeratin expression pattern showed a shift that was consistent with columnar epithelium. Involvement of the BMP pathway was suggested by up-regulation of Phosphorylated-Smad 1/5/8 (P-Smad 1/5/8) that was effectively blocked by Noggin, a BMP antagonist. Comparison of the gene expression profiles of squamous cells, BMP-4-treated squamous cells, and BE cells showed a significant shift in the profile of the BMP-4-treated squamous cells toward that of the cultured BE cells.


CONCLUSIONS
These results suggest that the BMP pathway could play a role in the transformation of normal esophageal squamous cells into columnar cells.
Milano
Francesca
F
Laboratory of Experimental Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
van Baal
Jantine W P M
JW
Buttar
Navtej S
NS
Rygiel
Agnieszka M
AM
de Kort
Floor
F
DeMars
Cathrine J
CJ
Rosmolen
Wilda D
WD
Bergman
Jacques J G H M
JJ
VAn Marle
Jan
J
Wang
Kenneth K
KK
Peppelenbosch
Maikel P
MP
Krishnadath
Kausilia K
KK
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001471:Barrett Esophagus / Q000378:metabolism* / Q000473:pathology*; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D004941:Esophagitis / Q000378:metabolism* / Q000473:pathology*; D004947:Esophagus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D015894:Genome, Human; D006801:Humans; D007633:Keratins / Q000378:metabolism; D008297:Male; D008679:Metaplasia; D046228:Microarray Analysis; D008875:Middle Aged; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley
C525809:BMP4 protein, human; C525811:Bmp4 protein, rat; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D007633:Keratins