Stromal hyperplasia in male bladders upon loss of transforming growth factor-beta signaling in fibroblasts.
OBJECTIVE
Rapid bladder growth associated, partial urethral obstruction and embryonic bladder development entail stromal-epithelial interactions involving signaling by the cytokine transforming growth factor-beta (TGF-beta). However, to our knowledge the role of TGF-beta in bladder stromal hyperplasia and hypertrophy is not understood.


METHODS
In an effort to understand the specific role of TGF-beta signaling in bladder stroma a fibroblast specific conditional knockout mouse of the type II TGF-beta 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-beta signaling in the lamina propria of bladders of male and female Tgfbr2(/spko), mice, and yet pronounced alpha-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-beta signaling in fibroblasts. Deletion of TGF-beta 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-beta signaling with estrogens and androgens in bladder fibrosis.
Sharif-Afshar
Ali-Reza
AR
Department of Urologic Surgery, Vanderbilt Children's Hospital, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Donohoe
Jeffrey M
JM
Pope
John C
JC
Adams
Mark C
MC
Brock
John W
JW
Bhowmick
Neil A
NA
D000818:Animals; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006965:Hyperplasia / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000172:deficiency / Q000502:physiology*; D001745:Urinary Bladder Diseases / Q000473:pathology*
D016212:Transforming Growth Factor beta