Introduction. Transforming growth factor-β1 (TGF-β1) has been known to play a crucial role in the pathogenesis of Peyronie's disease (PD). Aim. The aim of this paper was to investigate the therapeutic effect of IN-1130, a novel small molecule inhibitor of activin receptor-like kinase (ALK)5, a type I receptor of TGF-β, in an animal model of PD. Methods. PD was induced in rats through repeated injections of adenovirus expressing TGF-β1 (days 0, 3, and 6; 1 × 10 10 particles/0.1mL, respectively) into the tunica albuginea. The rats were divided into five groups (N = 10 per group): group 1, age-matched controls without treatment; group 2, age-matched controls receiving repeated injections of IN-1130 (days 30 and 37; 5 mg/kg in 0.1mL saline, respectively); group 3, PD rats without treatment; group 4, PD rats receiving repeated injections of saline (days 30 and 37; 0.1mL, respectively); group 5, PD rats receiving repeated injections of IN-1130 (days 30 and 37; 5 mg/kg in 0.1 mL saline, respectively) into the lesion. Main Outcome Measures. Penile curvature was evaluated by use ofan artificial erection test at day 45, and the penis was then harvested for histologic examination. Collagen in the plaque was quantitatively assessed by hydroxyproline determination. Results. IN-1130 induced significant regression of fibrotic plaque through reduced infiltration of inflammatory cells, reduced transnuclear expression of phospho-Smad2/phospho-Smad3, reduced hydroxyproline content, and reduced cartilage content and restoration of elastin fibers in the fibrotic plaque of PD rats, which was accompanied by the correction of penile curvature. Conclusion. Antagonizing TGF-β signaling through the use of ALK5 inhibitors may represent an exciting new therapeutic strategy for the future treatment of PD.
Bibliographical noteFunding Information:
This study was supported by grant no. R01-2005-000-10411-0 (Jun-Kyu Suh) and by grant no. R01-2007-000-10075-0 (Ji-Kan Ryu) from the Basic Research Program of the Korea Science and Engineering Foundation, and by grant no. 410053 from the Korea Research Foundation (Lu Wei Zhang and Jun-Kyu Suh). The authors thank Jennifer Holmes for help in preparing the manuscript.
- Peyronie's disease
- Transforming growth factor-beta