Purpose: Rapid bladder growth associated, partial urethral obstruction and embryonic bladder development entail stromal-epithelial interactions involving signaling by the cytokine transforming growth factor-β (TGF-β). However, to our knowledge the role of TGF-β in bladder stromal hyperplasia and hypertrophy is not understood. Materials and Methods: In an effort to understand the specific role of TGF-β signaling in bladder stroma a fibroblast specific conditional knockout mouse of the type II TGF-β receptor gene, Tgfbr2/spko, was generated using Cre-lox methodology. Bladders from 18, 7 to 8-week-old mice were harvested for histological and immunohistochemical analysis. Results: Bladders from homozygous Tgfbr2/ spko male mice showed marked hypertrophy in the lamina propria and smooth muscle layers in the absence of visible or functional bladder obstruction by age 8 weeks. However, age matched female mice of the same genotype maintained bladder architecture similar to that in wild-type littermate male and female controls. Immunohistochemistry for the phosphorylated form of Smad2 indicated a general loss in TGF-β signaling in the lamina propria of bladders of male and female Tgfbr2/spko mice, and yet pronounced α-smooth muscle actin expression was noted in male Tgfbr2/spko bladders, which is a marker for myofibroblasts. Conclusions: A sex disparity was observed in the Tgfbr2/spko mouse model lacking TGF-β signaling in fibroblasts. Deletion of TGF-β in males leads to a hypertrophied lamina propria and muscularis externa with myofibroblast differentiation and proliferation. Female homozygous Tgfbr2/spko bladders appeared the same as those of wild-type male and female controls. This model suggests a role for stromal TGF-β signaling with estrogens and androgens in bladder fibrosis.
- Transgenic mice
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