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HORMONES AND SIGNALING

Functional role of bone morphogenetic protein-4 in isolated canine parietal cells

Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan

Bone morphogenetic protein (BMP)-4 is an important regulator of cellular growth and differentiation. Expression of BMP-4 has been documented in the gastric mucosa. We reported that incubation of canine parietal cells with EGF for 72 h induced both parietal cell morphological transformation and inhibition of H⁺/K⁺-ATPase gene expression through MAPK-dependent mechanisms. We explored the role of BMP-4 in parietal cell maturation and differentiation. Moreover, we investigated if BMP-4 modulates the actions of EGF in parietal cells. H⁺/K⁺-ATPase gene expression was examined by Northern blots and quantitative RT-PCR. Acid production was assessed by measuring the uptake of [¹⁴C]aminopyrine. Parietal cell apoptosis was quantitated by Western blots with anti-cleaved caspase 3 antibodies and by counting the numbers of fragmented, propidium iodide-stained nuclei. MAPK activation and Smad1 phosphorylation were measured by Western blots with anti-phospho-MAPK and anti-phospho-Smad1 antibodies. Parietal cell morphology was examined by immunohistochemical staining of cells with anti-H⁺/K⁺-ATPase -subunit antibodies. BMP-4 stimulated Smad1 phosphorylation and induced H⁺/K⁺-ATPase gene expression. BMP-4 attenuated EGF-mediated inhibition of H⁺/K⁺-ATPase gene expression and blocked EGF induction of both parietal cell morphological transformation and MAPK activation. Incubation of cells with BMP-4 enhanced histamine-stimulated [¹⁴C]aminopyrine uptake. BMP-4 had no effect on parietal cell apoptosis, whereas TGF- stimulated caspase-3 activation and nuclear fragmentation. In conclusion, BMP-4 promotes the induction and maintenance of a differentiated parietal cell phenotype. These findings may provide new clues for a better understanding of the mechanisms that regulate gastric epithelial cell growth and differentiation.

Smad proteins; mitogen-activated protein kinases/extracellular signal-regulated kinases; cellular differentiation; apoptosis; gastric acid secretion