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Transforming Growth Factor (TGF)-β Type I Receptor Kinase (ALK5) Inhibitor Alleviates Profibrotic TGF-β1 Responses in Fibroblasts Derived from Peyronie’s Plaque
Abstract
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 (10 ng/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.
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NF-κB interacts with other signaling pathways implicated in PD, such as the TGF-β and Wnt/β-catenin pathways.
“Moreover, NF-κB has been shown to interact with other signaling pathways implicated in PD, such as the TGF-β and Wnt/β-catenin pathways.”
From Research advances in Peyronie's disease: a comprehensive review on genomics, pathways, phenotypic manifestation, and therapeutic targets. (2024) · cites this paper as [69]
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Understanding the course of Peyronie's disease
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Self-citationChi, J., Bi, W., Lou, K., Ma, J., Wu, J., & Cui, Y. (2024) · Sexual Medicine Reviews · doi:10.1093/sxmrev/qeae006 · Cited by 14
Drugs of the future for Peyronie’s disease
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Metadata
- Authors
- Piao, S., Choi, M. J., Tumurbaatar, M., Kim, W. J., Jin, H.-R., Shin, S. H., Tuvshintur, B., Yin, G. N., Song, J. S., Kwon, M.-H., Lee, S.-J., Han, J.-Y., Kim, S.-J., Ryu, J.-K., & Suh, J.-K.
- Affiliations
- Inha University (KR)
- National Cancer Center (KR)
- Gachon University (KR)
- Corresponding author
- Ryu, Ji-Kan
- Suh, Jun-Kyu
- ORCID
- Venue
- The Journal of Sexual Medicine
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-10-01
- Volume
- 7
- Issue
- 10
- Pages
- 3385-3395
- ISSN
- 1743-6095 (ISSN-L)
- 1743-6109
- OpenAlex
- W2124313358
- Cited by
- 38
- References
- 3
- Citations by year
- 2026: 1 · 2024: 4 · 2023: 3 · 2021: 2 · 2020: 3 · 2019: 1 · 2018: 2 · 2015: 1 · 2014: 4 · 2013: 7 · 2012: 5
- FWCI
- 3.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- The Journal of Sexual Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Korea Science and Engineering Foundation
- Ministry of Education, Science and Technology
- Topics
- Health Sciences › Medicine › Rheumatology › Dupuytren's Contracture and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Urology › Urological Disorders and Treatments
- Keywords
- TGF-β1, ALK5 inhibitor, Smad2/3 phosphorylation, fibroblasts, plaque fibrosis, extracellular matrix, tunica albuginea, antifibrotic therapy, Smad nuclear translocation
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type I, Adult, Aged, Cells, Cultured, Extracellular Matrix, Fibroblasts, Humans, Male, Middle Aged, Penile Induration, Penis, Phosphorylation, Blotting, Western, Protein Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Active Transport, Cell Nucleus, Smad2 Protein, Smad3 Protein, Transforming Growth Factor beta1
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