Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) and Its Death Receptor (DR5) in Peyronie’s Disease. A Biomolecular Study of Apoptosis Activation Carla Loreto, MD,* Guido Barbagli, MD, † Rados Djinovic, MD, ‡ Giuseppe Vespasiani, MD, § Maria Luisa Carnazza, MD,* Roberto Miano, MD, § Giuseppe Musumeci, PhD,* and Salvatore Sansalone, MD § *Department of Anatomy, Diagnostic Pathology, Forensic Medicine, Hygiene and Public Health, University of Catania, Italy; † Centre for Reconstructive Urethral Surgery, Arezzo, Italy; ‡ Serbian Academy of Science and Arts, School of Medicine, University of Belgrade, Serbia; § Department of Urology, School of Medicine Tor Vergata University of Rome, Rome, Italy DOI: 10.1111/j.1743-6109.2010.02003.x ABSTRACT Introduction. Peyronie’s disease (PD) is a connective tissue disorder of tunica albuginea (TA), a thick fibrous sheath surrounding the corpora cavernosa of the penis. Relatively, little is known about the disease itself. Aim. To investigate whether the apoptosis cascade in degenerated and macroscopically deformed TA from men with PD is activated through the extrinsic pathway, by assessing the immunoexpression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptor, DR5. Methods. TA plaques from 15 men with PD and from four unaffected men were processed for TRAIL and DR5 immunohistochemistry and Western blot analysis. Main Outcome Measures. A greater understanding of the pathophysiology of PD through a molecular approach, to gain insights that may lead to novel forms of treatment. Results. Activation of the apoptosis mechanisms through the extrinsic pathway was demonstrated by TRAIL and DR5 overexpression in fibroblasts and myofibroblasts from affected TA. Conclusion. The finding that apoptosis activation in TA plaques occurs, at least in part, via the extrinsic pathway may help devise novel therapeutic options for these patients. Loreto C, Barbagli G, Djinovic R, Vespasiani G, Carnazza ML, Miano R, Musumeci G, Sansalone S. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptor (DR5) in Peyronie’s disease. A biomolecular study of apoptosis activation. J Sex Med **;**:**–**. Key Words. Peyronie’s Disease; Peyronie’s Plaque Healing; Apoptosis; TRAIL; DR5 Introduction P eyronie’s disease (PD) is a connective tissue disorder of the tunica albuginea (TA), a thick fibrous sheath surrounding the corpora cavernosa of the penis [1–4]. It affects 2–3% of the male population between the 4th and the 6th decade [5,6] and is characterized clinically by plaques, penis deformation, localized pain, and erectile dysfunction. The initiating event in plaque devel- opment seems to be an external stress received most likely in the erect state, usually during sexual activity [7]. There is growing consensus that the resulting TA injury or tear heals abnor- mally, although the underlying mechanism is unclear [6,8–11]. Some researchers view PD plaques as scars that have failed to remodel well [11]. Relatively little is known about the disease itself; this is also reflected in the lack of effective treatments capable of altering its course or pro- gression [7,12]. A greater understanding of the pathophysiology of PD at the molecular level may provide insights and lead to novel forms of treatment. 1 © 2010 International Society for Sexual Medicine J Sex Med **;**:**–**