Transforming Growth Factor (TGF)-β Type I Receptor Kinase (ALK5) Inhibitor Alleviates Profibrotic TGF-β1 Responses in Fibroblasts Derived from Peyronie's Plaque
Transforming Growth Factor (TGF)-β Type I Receptor Kinase (ALK5) Inhibitor Alleviates Profibrotic TGF-β1 Responses in Fibroblasts Derived from Peyronie's Plaque
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DOI：
10.1111/j.1743-6109.2010.01753.x
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发表时间：
2010-10-01
影响因子：
3.5
通讯作者：
Suh, Jun-Kyu
中科院分区：
文献类型：
--
作者：
Piao, Shuguang;Choi, Min Ji;Suh, Jun-Kyu
简介。转化生长因子-β 1 (TGF-β 1) 已被确定为与佩罗尼氏病 (PD) 相关的重要纤维化细胞因子。目的。本研究的目的是研究 PD 患者斑块组织中 TGF-β 1 和 Smad 转录因子的差异表达，并确定 SKI2162（SK Chemicals，首尔，韩国）的抗纤维化作用，SKI2162 是一种新型激活素受体样激酶 5 小分子抑制剂(ALK5)，一种 TGF-β 的 I 型受体，存在于人 PD 斑块来源的原代成纤维细胞中。方法：从 5 名 PD 患者中分离斑块组织，从 4 名对照患者中获得白膜组织。来自 PD 患者的斑块组织用于原代成纤维细胞培养。用SKI2162 (10 μM)预处理成纤维细胞，然后用TGF-β 1 (10 ng/mL)刺激。主要结果测量。用Masson三色或TGF-β 1、磷酸-Smad2 (P-Smad2)和P-Smad3抗体对斑块或白膜组织进行染色。从处理过的成纤维细胞中提取蛋白质进行蛋白质印迹，并用 P-Smad2/Smad2、P-Smad3/Smad3、纤溶酶原激活剂抑制剂-1、纤连蛋白、胶原蛋白 I 和胶原蛋白 IV 的抗体探测膜。我们还确定了 SKI2162 对 TGF-β 1 诱导的成纤维细胞中 Smad2/3 核转位的抑制作用。结果。PD 患者的斑块组织比对照患者的白膜组织显示出更高的 TGF-β 1、P-Smad2 和 P-Smad3 免疫反应性。 SKI2162不仅阻断TGF-β1诱导的Smad2和Smad3的磷酸化和核转位，而且还抑制人PD斑块来源的成纤维细胞中细胞外基质标志物的产生。结论。鉴于TGF-β和Smads在PD发病机制中的关键作用，药物抑制ALK5可能代表治疗PD的一种新的靶向方法。 Piao S、Choi MJ、Tumurbaatar M、Kim WJ、Jin H-R、Shin SH、Tuvshintur B、Yin GN、Song JS、Kwon M-H、Lee S-J、Han J-Y、Kim S-J、Ryu J-K 和 Suh J-K。转化生长因子 (TGF)-β I 型受体激酶 (ALK5) 抑制剂可减轻佩罗尼斑块来源的成纤维细胞中的促纤维化 TGF-β 1 反应。 《性医学杂志》2010 年；7：3385-3395。
Introduction.Transforming growth factor-beta 1 (TGF-beta 1) has been identified as an important fibrogenic cytokine associated with Peyronie's disease (PD).Aim.The aim of this study was to study the differential expression of the TGF-beta 1 and Smad transcription factors in plaque tissue from PD patients and to determine the antifibrotic effect of SKI2162 (SK Chemicals, Seoul, South Korea), a novel small-molecule inhibitor of activin receptor-like kinase 5 (ALK5), a type I receptor of TGF-beta, in primary fibroblasts derived from human PD plaque.Methods.Plaque tissue was isolated from five PD patients, and tunica albuginea tissue was obtained from four control patients. Plaque tissues from a patient with PD were used for primary fibroblast culture. Fibroblasts were pretreated with SKI2162 (10 mu M) and then stimulated with TGF-beta 1 (10 ng/mL).Main Outcome Measures.The plaque or tunica albuginea tissue was stained with Masson's trichrome or antibody to TGF-beta 1, phospho-Smad2 (P-Smad2), and P-Smad3. Protein was extracted from treated fibroblasts for Western blotting, and the membranes were probed with antibody to P-Smad2/Smad2, P-Smad3/Smad3, plasminogen activator inhibitor-1, fibronectin, collagen I, and collagen IV. We also determined the inhibitory effect of SKI2162 on TGF-beta 1-induced nuclear translocation of Smad2/3 in fibroblasts.Results.The plaque tissue from PD patients showed higher TGF-beta 1, P-Smad2, and P-Smad3 immunoreactivity than did the tunica albuginea tissue from control patients. SKI2162 not only blocked TGF-beta 1-induced phosphorylation and nuclear translocation of Smad2 and Smad3, but also inhibited the production of extracellular matrix markers in fibroblasts derived from human PD plaque.Conclusion.In light of the pivotal role of TGF-beta and Smads in the pathogenesis of PD, pharmacologic inhibition of ALK5 may represent a novel targeted approach to treating PD. Piao S, Choi MJ, Tumurbaatar M, Kim WJ, Jin H-R, Shin SH, Tuvshintur B, Yin GN, Song JS, Kwon M-H, Lee S-J, Han J-Y, Kim S-J, Ryu J-K, and Suh J-K. Transforming growth factor (TGF)-beta type I receptor kinase (ALK5) inhibitor alleviates profibrotic TGF-beta 1 responses in fibroblasts derived from Peyronie's plaque. J Sex Med 2010;7:3385-3395.