Stromal hyperplasia in male bladders upon loss of transforming growth factor-β signaling in fibroblasts

Ali Reza Sharif-Afshar, Jeffrey M. Donohoe, John C. Pope IV, Mark C. Adams, John W. Brock, Neil A. Bhowmick, Paul F. Austin, Richard Grady, Eric Kurzrock

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14 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1704-1707
Number of pages4
JournalJournal of Urology
Volume174
Issue number4 II
DOIs
StatePublished - Oct 2005

Keywords

  • Bladder
  • Fibroblast
  • Tgf-beta
  • Transgenic mice

ASJC Scopus subject areas

  • Urology

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    Sharif-Afshar, A. R., Donohoe, J. M., Pope IV, J. C., Adams, M. C., Brock, J. W., Bhowmick, N. A., Austin, P. F., Grady, R., & Kurzrock, E. (2005). Stromal hyperplasia in male bladders upon loss of transforming growth factor-β signaling in fibroblasts. Journal of Urology, 174(4 II), 1704-1707. https://doi.org/10.1097/01.ju.0000164720.72732.9c