The journal of sexual medicine · 2010
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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Piao Shuguang, Choi Min Ji, Tumurbaatar Munkhbayar, Kim Woo Jean, Jin Hai-Rong, Shin Sun Hwa, Tuvshintur Buyankhuu, Yin Guo Nan, Song Jae Sook, Kwon Mi-Hye, Lee Sang-Jin, Han Jee-Young, Kim Seong-Jin, Ryu Ji-Kan, Suh Jun-Kyu
Аннотация
INTRODUCTION: Transforming growth factor-β1 (TGF-β1) 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-β1 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-β, 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 µM) and then stimulated with TGF-β1 (10ng/mL).
MAIN OUTCOME MEASURES: The plaque or tunica albuginea tissue was stained with Masson's trichrome or antibody to TGF-β1, 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-β1-induced nuclear translocation of Smad2/3 in fibroblasts.
RESULTS: The plaque tissue from PD patients showed higher TGF-β1, P-Smad2, and P-Smad3 immunoreactivity than did the tunica albuginea tissue from control patients. SKI2162 not only blocked TGF-β1-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-β and Smads in the pathogenesis of PD, pharmacologic inhibition of ALK5 may represent a novel targeted approach to treating PD.
AIM: The aim of this study was to study the differential expression of the TGF-β1 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-β, 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 µM) and then stimulated with TGF-β1 (10ng/mL).
MAIN OUTCOME MEASURES: The plaque or tunica albuginea tissue was stained with Masson's trichrome or antibody to TGF-β1, 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-β1-induced nuclear translocation of Smad2/3 in fibroblasts.
RESULTS: The plaque tissue from PD patients showed higher TGF-β1, P-Smad2, and P-Smad3 immunoreactivity than did the tunica albuginea tissue from control patients. SKI2162 not only blocked TGF-β1-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-β and Smads in the pathogenesis of PD, pharmacologic inhibition of ALK5 may represent a novel targeted approach to treating PD.
Предметные рубрики MeSH
Active Transport, Cell NucleusAdultAgedBlotting, WesternCells, CulturedExtracellular MatrixFibroblastsHumansMaleMiddle AgedPenile IndurationPenisPhosphorylationProtein Serine-Threonine KinasesReceptor, Transforming Growth Factor-beta Type IReceptors, Transforming Growth Factor betaSmad2 ProteinSmad3 ProteinTransforming Growth Factor beta1