Sharif-Afshar Ali-Reza, Donohoe Jeffrey M, Pope John C, Adams Mark C, Brock John W, Bhowmick Neil A
Department of Urologic Surgery, Vanderbilt Children's Hospital, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
J Urol. 2005 Oct;174(4 Pt 2):1704-7; discussion 1707. doi: 10.1097/01.ju.0000164720.72732.9c.
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.
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.
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.
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.
膀胱快速生长、部分尿道梗阻以及胚胎膀胱发育均涉及基质 - 上皮相互作用，其中细胞因子转化生长因子 -β（TGF-β）发挥信号传导作用。然而，据我们所知，TGF-β在膀胱基质增生和肥大中的作用尚不清楚。
为了了解TGF-β信号在膀胱基质中的具体作用，我们使用Cre-lox方法构建了成纤维细胞特异性条件性敲除II型TGF-β受体基因（Tgfbr2(/spko)）的小鼠模型。收集18只7至8周龄小鼠的膀胱进行组织学和免疫组织化学分析。
纯合Tgfbr2(/spko)雄性小鼠的膀胱在8周龄时，固有层和平滑肌层出现明显肥大，且无明显可见的或功能性膀胱梗阻。然而，相同基因型的年龄匹配雌性小鼠的膀胱结构与野生型同窝雄性和雌性对照相似。对Smad2磷酸化形式的免疫组织化学分析表明，雄性和雌性Tgfbr2(/spko)小鼠膀胱固有层中的TGF-β信号普遍缺失，但在雄性Tgfbr2(/spko)膀胱中观察到明显的α-平滑肌肌动蛋白表达，这是肌成纤维细胞的标志物。
在成纤维细胞中缺乏TGF-β信号的Tgfbr2(/spko)小鼠模型中观察到了性别差异。雄性小鼠中TGF-β的缺失导致固有层和外肌层肥大，并伴有肌成纤维细胞的分化和增殖。雌性纯合Tgfbr2(/spko)膀胱与野生型雄性和雌性对照相同。该模型表明基质TGF-β信号与雌激素和雄激素在膀胱纤维化中发挥作用。
