Bone morphogenetic protein 2 is expressed by, and acts upon, mature epithelial cells in the colon.
OBJECTIVE
The recent findings of bone morphogenetic protein (BMP) receptor Ia mutations in juvenile polyposis and frequent Smad4 mutations in colon cancer suggest a role for BMPs in the colonic epithelium and colon cancer. We investigated the role of BMP2 in the colon.


METHODS
We assessed BMP receptor expression in cell lines using the reverse-transcribed polymerase chain reaction and immunoblotting. We investigated the effect of BMP2 on cell lines using the MTT assay and by immunoblotting for markers of differentiation, proliferation, and apoptosis. We assessed the expression of BMP2, its receptors, and signal transduction elements in mouse and human colon tissue using immunohistochemistry. We also investigated the effect of the BMP antagonist noggin in vivo in mice by assessing colon tissue with immunohistochemistry and immunoblotting. Finally, we investigated the expression of BMP2 in microadenomas from familial adenomatous polyposis patients.


RESULTS
BMP receptors (BMPR) Ia, BMPR Ib, and BMPR II are all expressed in colonic epithelial cell lines. BMP2 inhibits colonic epithelial cell growth in vitro, promoting apoptosis and differentiation and inhibiting proliferation. BMP2, BMPRIa, BMPRIb, BMPRII, phosphorylated Smad1, and Smad4 are expressed predominantly in mature colonocytes at the epithelial surface in normal adult human and mouse colon. Noggin inhibits apoptosis and proliferation in mouse colonic epithelium in vivo. BMP2 expression is lost in the microadenomas of familial adenomatous polyposis patients.


CONCLUSIONS
These data suggest that BMP2 acts as a tumor suppressor promoting apoptosis in mature colonic epithelial cells.
Hardwick
James C H
JC
Department of Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands. J.C.Hardwick@amc.uva.nl
Van Den Brink
Gijs R
GR
Bleuming
Sylvia A
SA
Ballester
Isabel
I
Van Den Brande
Jan M H
JM
Keller
Josbert J
JJ
Offerhaus
G Johan A
GJ
Van Deventer
Sander J H
SJ
Peppelenbosch
Maikel P
MP
D011125:Adenomatous Polyposis Coli / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D055396:Bone Morphogenetic Protein 2; D052004:Bone Morphogenetic Protein Receptors; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D002352:Carrier Proteins; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003106:Colon / Q000378:metabolism / Q000503:physiopathology*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000494:pharmacology; D017978:Receptors, Growth Factor / Q000378:metabolism; D051785:Smad Proteins; D051898:Smad1 Protein; D051901:Smad4 Protein; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism; D016212:Transforming Growth Factor beta; D051176:beta Catenin; D000099176:Noggin Protein
D055396:Bone Morphogenetic Protein 2; D052004:Bone Morphogenetic Protein Receptors; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D017978:Receptors, Growth Factor; D051785:Smad Proteins; D051898:Smad1 Protein; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D051176:beta Catenin; D000099176:Noggin Protein; C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C497399:SMAD1 protein, human; C497796:SMAD4 protein, human; C497401:Smad1 protein, mouse; C490810:Smad4 protein, mouse; C498211:BMPR1A protein, human; C498214:BMPR1B protein, human; C498218:BMPR2 protein, human; C498212:Bmpr1a protein, mouse; C498215:Bmpr1b protein, mouse; C498219:Bmpr2 protein, mouse