Bone morphogenetic protein signaling regulates gastric epithelial cell development and proliferation in mice.
OBJECTIVE
We investigated the role of bone morphogenetic protein (BMP) signaling in the regulation of gastric epithelial cell growth and differentiation by generating transgenic mice that express the BMP inhibitor noggin in the stomach.


METHODS
The promoter of the mouse H+/K+-ATPase β-subunit gene, which is specifically expressed in parietal cells, was used to regulate expression of noggin in the gastric epithelium of mice. The transgenic mice were analyzed for noggin expression, tissue morphology, cellular composition of the gastric mucosa, gastric acid content, and plasma levels of gastrin. Tissues were analyzed by immunohistochemical, quantitative real-time polymerase chain reaction, immunoblot, microtitration, and radioimmunoassay analyses.


RESULTS
In the stomachs of the transgenic mice, phosphorylation of Smad 1, 5, and 8 decreased, indicating inhibition of BMP signaling. Mucosa were of increased height, with dilated glands, cystic structures, reduced numbers of parietal cells, and increased numbers of cells that coexpressed intrinsic factor, trefoil factor 2, and Griffonia (Bandeiraea) simplicifolia lectin II, compared with wild-type mice. In the transgenic mice, levels of the H+/K+-ATPase α-subunit protein and messenger RNA were reduced, whereas those of intrinsic factor increased. The transgenic mice were hypochloridric and had an increased number of Ki67- and proliferating cell nuclear antigen-positive cells; increased levels of plasma gastrin; increased expression of transforming growth factor-α, amphiregulin, and gastrin; and activation of extracellular signal-regulated kinase 2.


CONCLUSIONS
Inhibiting BMP signaling in the stomachs of mice by expression of noggin causes loss of parietal cells, development of transitional cells that express markers of mucus neck and zymogenic lineages, and activation of proliferation. BMPs are therefore important regulators of gastric epithelial cell homeostasis.
Shinohara
Masahiko
M
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
Mao
Maria
M
Keeley
Theresa M
TM
El-Zaatari
Mohamad
M
Lee
Hyuk-Joon
HJ
Eaton
Kathryn A
KA
Samuelson
Linda C
LC
Merchant
Juanita L
JL
Goldenring
James R
JR
Todisco
Andrea
A
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D019872:Chief Cells, Gastric / Q000166:cytology / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism; D007437:Intrinsic Factor / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009077:Mucins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D010295:Parietal Cells, Gastric / Q000166:cytology / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D037121:Plant Lectins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013270:Stomach / Q000166:cytology*; D000071164:Trefoil Factor-2; D000099176:Noggin Protein
D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D007437:Intrinsic Factor; D009077:Mucins; D009124:Muscle Proteins; D010455:Peptides; D037121:Plant Lectins; D000071164:Trefoil Factor-2; D000099176:Noggin Protein; C045475:Griffonia simplicifolia lectins; C481546:TFF2 protein, mouse
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