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Tumor necrosis factorrelated apoptosisinducing ligand (trail) and its death receptor (dr5) in peyronie's disease. a biomolecular study of apoptosis activation

Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand
(TRAIL) and Its Death Receptor (DR5) in Peyronie's Disease.
A Biomolecular Study of Apoptosis Activationjsm_20031.7

Carla Loreto, MD,* Guido Barbagli, MD,† Rados Djinovic, MD,‡ Giuseppe Vespasiani, MD,§Maria Luisa Carnazza, MD,* Roberto Miano, MD,§ Giuseppe Musumeci, PhD,* andSalvatore 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 ofMedicine, University of Belgrade, Serbia; §Department of Urology, School of Medicine Tor Vergata University of Rome,Rome, Italy A B S T R A C T
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
sexual activity [7]. There is growing consensusthat the resulting TA injury or tear heals abnor- P eyronie's disease (PD) is a connective tissue mally, although the underlying mechanism is disorder of the tunica albuginea (TA), a thick unclear [6,8–11]. Some researchers view PD fibrous sheath surrounding the corpora cavernosa plaques as scars that have failed to remodel well of the penis [1–4]. It affects 2–3% of the male [11]. Relatively little is known about the disease population between the 4th and the 6th decade itself; this is also reflected in the lack of effective [5,6] and is characterized clinically by plaques, treatments capable of altering its course or pro- penis deformation, localized pain, and erectile gression [7,12]. A greater understanding of the dysfunction. The initiating event in plaque devel- pathophysiology of PD at the molecular level opment seems to be an external stress received may provide insights and lead to novel forms of most likely in the erect state, usually during 2010 International Society for Sexual Medicine J Sex Med **;**:**–** Loreto et al. The working hypothesis of this study was that after intracavernous injection of alprostadil apoptosis, or programmed cell death, may be implicated in PD. Apoptosis is a tightly regulated The control samples were from four patients process involved in embryogenesis, metamorpho- (mean age 23 ⫾ 3.0 years; range 21–27) with con- sis, normal tissue turnover, wound healing, and a genital penile curvature, who underwent Nesbit's variety of pathological conditions resulting from corrective procedure [17]. Their clinical histories its dysregulation, whose function is to remove were negative for generalized penile diseases harmful, damaged, or unwanted cells [13]. This and none had macroscopic signs of degenerative homeostatic mechanism acts through two main or inflammatory disorders. Staining of these pathways: the extrinsic (or death receptor- specimens with Mayer's hematoxylin showed no mediated) and the intrinsic (or mitochondrial).
detectable pathological abnormalities on light The former involves activation of death signaling ligands, like tumor necrosis factor (TNF)-a, FasL,tumor necrosis factor-related apoptosis-inducingligand (TRAIL; a recently identified death factor that acts as a potent apoptosis inducer and activates For the immunohistochemical studies, the TA its death receptors DR4 and DR5), and members samples were fixed overnight in 10% neutral buff- of the TNF-receptor superfamily (e.g., TNF ered formalin (Bio-Optica, Milan, Italy) and then receptor I, DR4, and DR5), which results in acti- demineralized in ethylenediaminetetraacetic acid vation of caspase 8, that in turn cleaves—hence (EDTA) decalcification fluid (41.3 g disodium activates—the proenzyme form of caspase 3, an EDTA, 4.4 g NaOH in 1,000 mL distilled water) executioner caspase. The latter enzyme then per- for 6 weeks at 4°C. After fixation and overnight forms its executioner role by destroying the cell's washing, they were dehydrated in graded ethanol cytoskeletal and reparative proteins [14,15], a and embedded in paraffin. Specimens were then process that culminates with DNA fragmentation.
sectioned at a thickness of 5 mm and placed on We investigated whether the extrinsic pathway silanized glass slides. Endogenous peroxidase participates in apoptosis activation by assessing the activity was quenched by treatment with 3% immunoexpression of TRAIL and its death recep- H2O2 for 10 minutes. Nonspecific antibody tor, DR5, in TA plaques to gain insights into the binding was blocked by treatment with normal molecular activation of programmed cell death in horse/goat serum (dil. 1:20 in phosphate buffered PD. To our knowledge, there are no similar animal saline, 0.1% bovine serum albumin). Sections were or human studies.
irradiated (5 minutes ¥ 3) in capped polypropyleneslide-holders with citrate buffer (pH 6), using amicrowave oven (750 W) to unmask antigen sites.
Materials and Methods
Antibodies for localization of TRAIL and DR5 Patients and Tissues were rabbit polyclonal anti-TRAIL (Santa Cruz Biopsy specimens (wedge shaped, approximately Biotechnology, Inc., Santa Cruz, CA, USA) and 5 ¥ 3 mm) were collected from 15 patients (mean anti-DR5 (Novus Biologicals, Littleton, CO, age 53 ⫾ 10 years; range 31–67) with stable PD for USA) used at 1:100 working dilutions. They were at least 6 months at the level of the corporotomy applied directly onto sections and slides were incu- during corrective surgery for PD. All patients bated overnight (4°C) in a humid chamber.
underwent albugineal grating using the geometri- Immune complexes were then treated with a bioti- cal principle, as originally described by Egydio nylated link antibody and then detected with [16]. The TA was incised and grafted at the level of peroxidase-labeled streptavin, both incubated for the maximum curvature, where plaque was most 10 minutes at room temperature (LSAB + System- HRP, Dako Italia SPA, Milan, Italy).
The study was approved by the local ethics The immunoreaction was examined with an committee. The informed consent of each patient Axioplan light microscope (Zeiss, Oberkochen, was obtained before tissue collection.
Germany) after incubating sections in 0.1% 3,3′- On preoperative examination, all patients diaminobenzidine and 0.02% hydrogen peroxide reported spontaneous erections, but being pre- solution (DAB substrate kit, Vector Laboratories, vented from having regular sexual intercourse by a Burlingame, CA, USA) for 4 minutes. Sections penile curvature >45°. Degree of curvature and were lightly counterstained with Mayer's hema- rigidity were evaluated with Doppler ultrasound J Sex Med **;**:**–** Apoptosis in Peyronie's Disease Sweden) and finally mounted on GVA mount and with a secondary peroxidase-conjugated anti- (Zymed Laboratories, San Francisco, CA, USA).
rabbit (Amersham Pharmacia Biotech; 1:10,000)antibody or a polyclonal rabbit anti-DR5 antibody (Santa Cruz Biotechnology). Detection was per- The intensity of TRAIL and DR5 staining and the formed with a chemiluminescence assay (ECL; proportion of immunopositive cells were exam- Amersham Italia, Milano, Italy).
ined in blind by light microscopy and recorded by All experiments were performed at least three two anatomists and a histologist. Intensity of stain- times and the signal intensity was analyzed using a ing (IS) was graded in a semiquantitative manner digital imaging analysis system (1D Image Analysis using a 5-point scale, as follows: 0 = no detectable Software; Scientific Imaging Kodak, New Haven, staining, 1 = weak staining, 2 = moderate staining, CT, USA). b-tubulin (Santa Cruz Biotechnology) 3 = strong staining, 4 = very strong staining. The was used as an internal control to validate the right proportion of TRAIL- and DR5-immunopositive amount of protein loaded onto the gels.
cells (extent score = ES) was evaluated indepen- Densitometric analysis was expressed as inte- dently by two anatomists and a histologist and grated density by normalizing sample values to the scored as a proportion of 200 cells into four cat- corresponding b-tubulin expression.
3 = >50%, and 4 = >75%. Counting was per-formed at 200¥ magnification. The final staining score (FSS) was the sum of IS + ES.
Mean and standard deviation (SD) were calculatedfor the FSS. All data were analyzed with the SPSS Positive and Negative Controls program (SPSS® release 16.0, Chicago, IL, USA).
Positive and negative controls were performed totest the specific reaction of primary antibodies atthe protein level. For positive control testing, basal cell carcinoma tissue was exposed to an immunop-eroxidase process. Immunolabeling for TRAIL Histological examination of hematoxylin-stained and DR5 was found both in membranes and cyto- specimens showed that the collagen fiber arrange- plasm. For negative controls, TA plaques were ment was affected to different extents in all PD treated with normal rabbit serum instead of the samples, with damage ranging from fiber fragmen- tation to tears and splitting. The normal collagenfiber arrangement and ordered appearance was predominantly lost. The elastic fibers were often Fresh TA tissue was homogenized in a Polytron fragmented; in some cases, the collagen bundles homogenizer using a lysis buffer containing formed clumps with surrounding elastic fibers.
150 mM NaCl, 50 mM Tris–HCl (pH 7.5), 5 mM In contrast, the control TA samples showed EDTA, 1 mM Na3VO4, 30 mM Na pyrophos- preserved collagen bundles, with longitudinal fiber phate, 50 mM NaF, 1 mM acid phenyl-methyl- orientation in the outer layer and circular bundles sulfonyl-fluoride, 5 mg/mL aprotinin, 2 mg/mL in the inner layer.
leupeptin, 1 mg/mL pepstatin, 10% glycerol, and Immunohistochemical examination of PD sec- 0.2% Triton X-100. The homogenates were then tions showed immunoexpression of both TRAIL centrifuged at 14,000 rpm for 10 minutes at 4°C.
and DR5 in fibroblasts and myofibroblasts (2–3), The protein concentration of the supernatant was respectively, in the cytoplasm and in membrane determined by the Bradford method [18].
and cytoplasm (Figures 1 and 2), whereas few orno immunostained cells were observed in control Western Blot Analysis samples (1) (Figure 3). The proportion of immu- Equal amounts of protein were subjected to nopositive cells and the intensity of the immunore- sodium dodecyl sulfate–polyacrylamide gel elec- action in PD patients were much higher than in trophoresis on 10% gels, transferred onto Hybond normal tissue. The mean FSS of TA plaques was ECL nitrocellulose membranes (Amersham Phar- 4.77 ⫾ 0.61 (range 3.6–5.6).
macia Biotech, Amersham, UK) for 1 hour, and Western blot analysis of PD samples showed analyzed by immunoblotting with a primary poly- significantly increased TRAIL expression associ- clonal anti-TRAIL antibody (BD Transductions ated with constitutive expression of DR5 receptor Laboratories, Franklin Lakes, NJ, USA; 1:1.000), protein (Figure 4).
J Sex Med **;**:**–** Loreto et al. Figure 1 TRAIL immunostaining in a
tunica albuginea plaque from a subject
with Peyronie's disease (A) (¥40). (B)
Magnification of the inset in (A):
TRAIL-positive fibroblast and myofi-
broblast cells.
Using a TGF-b1-injected rat model, El-Sakka and colleagues documented an increase in myofi- To the best of our knowledge, this is the first study broblast content, endogenous TGF-b1 expression addressing some molecules critically implicated in and collagen synthesis in diseased TA [22–27] the TA apoptotic cascade in PD patients. In this similar to those seen in human PD. These charac- preliminary investigation, we focused on the acti- teristics are accompanied by an increase in reactive vation of the extrinsic pathway and DR5 expres- oxygen species (ROS), a well-known profibrotic sion. The disease is characterized by localized TA factor, and in inducible nitric oxide synthase disruption, a local increase in microvascular per- (iNOS), a recently recognized antifibrotic com- meability, persistent fibrin (deficient fibrinolysis) pound, whose induction may arise as a defense and collagen buildup, perivascular inflammation, mechanism against oxidative stress and fibrosis.
disruption and loss of elastic fibers, disorganized The iNOS nitric oxide (NO) quenches ROS by collagen bundles, increased synthesis of trans- forming peroxynitrite, an inducer of fibroblast and forming growth factor b1 (TGF-b1), and cell- and myofibroblast apoptosis [24–26,28,29].
collagen fiber-mediated contraction of pathologi- TGF-b1 is a multifunctional cytokine that cal TA, with eventual calcification and ossification inhibits growth and induces apoptosis of rat liver [1–4,8–11,19–21]. Scanty data are available on the epithelial cells [30]; apoptosis is blocked if TGF-b1 molecular mechanisms underlying PD.
expression is downregulated [31]. TGF-b1 can also Figure 2 DR5 immunostaining in a
tunica albuginea plaque from a subject
with Peyronie's disease (A) (¥40). (B)
Magnification of the inset in (A): DR5-
positive fibroblast and myofibroblast
cells.
Figure 3 Immunostaining for TRAIL
(A) and its receptor DR5 (B) in control
samples of tunica albuginea from a
subject without Peyronie's disease
(¥20).
J Sex Med **;**:**–**


Apoptosis in Peyronie's Disease Figure 4 Expression of TRAIL and its
death receptor DR5 in TA plaques from
a patient with Peyronie's disease.
Panel A: integrated density of the
Western
*P < 0.05 vs.
control values; Panel B: Western blotanalysis of proteins in TA plaques froma patient with Peyronie's disease.
Upper blot: TRAIL expression; middleblot: expression of DR5 death recep-tor; control; PD: Peyronie's disease.
influence fibroblast survival and induce fibrosis in and the halting of fibrosis progression. However, it chronic inflammatory disorders [31–33].
should be considered that after its activation, the TRAIL is a member of the TNF family of apoptosis process could be blocked by endogenous ligands, capable of initiating apoptosis through apoptosis inhibitors. Further studies are therefore engagement of its death receptors (DR4, DR5). It needed to gain insights into this delicate process.
selectively induces apoptosis of a variety of tumor Apoptosis of TA cells may also be triggered by and transformed cells, but not of most normal cells increased tissue tension and compression, as dem- [34], and has been seen to play a large role in cell onstrated in vitro in intervertebral discs, where it regulation and in inflammation processes [35,36].
has been suggested that a threshold of tissue strain Overall, four different receptors have been identi- initiates programmed cell death in the anulus fied that interact with TRAIL, the two death- fibrosus [42]; it has also been demonstrated that inducing receptors, DR4 and DR5, and DcR1 and myofibroblasts are more than likely to play a DcR2 (decoy receptors), which do not induce central role in mechanotransduction [43,44]. Con- death upon ligation and are believed to counteract sidering that cells are likely to play a substantial TRAIL-induced cytotoxicity [37]. DR5 is a widely role in tissue turnover, and that tissue degenera- investigated apoptosis molecule, also in a number tion seems to be associated to a loss of cellularity of tissue diseases that correlate with degenerative through apoptosis-related processes, the latter process may lead to decreased extracellular matrix generation and affect tissue organization and myofibroblast proliferation and accumulation of repair mechanisms [38]. In this regard, we demon- extracellular matrix [41]. In particular, TGF-b1 strated through TRAIL and DR5 upregulation promotes a fibroblast-to-myofibroblast transition that apoptosis activation could be responsible for that is initially followed by myofibroblast replica- tissue degeneration besides being a defense tion and activation, leading to an excess of collagen synthesis. In normal healing, a protective mecha- Despite a well-recognized effect on the TA, age nism achieves myofibroblast clearance through the does not seem to influence the tissue expression of apoptosis process. If the mechanism fails, persis- the apoptosis molecules in a significant way, as tence of these cells induces fibrosis with collagen inferred from studies of intervertebral and tem- accumulation and tissue contraction [7]. In this poromandibular disc programmed cell death regard, we documented activation of the mecha- involving experimental and control groups with nism through overexpression of DR5 and its very different mean ages [38,45] or describing a ligand, which could underpin plaque stabilization lack of statistical correlation with age [46].
J Sex Med **;**:**–** Loreto et al. This work documented activation of apoptosis (b) Revising It for Intellectual Content
through the extrinsic pathway in fibroblasts and Guido Barbagli; Rados Djinovic myofibroblasts from PD patients as overexpressionof TRAIL and its death receptor, DR5. We intend Category 3 to follow up on these findings by exploring other (a) Final Approval of the Completed Manuscript
molecules involved in programmed cell death.
Carla Loreto; Salvatore Sansalone Further research efforts could be extended toaddress the intrinsic pathways and executive caspases. We are also interested in investigatingthe action of TRAIL on fibroblast cell lines and on 1 Jordan GH, Schlossberg SM, Devine CJ. Surgery of the penis and urethra. In: Walsh PC, Retik AB, Vaughan ED, Wein AJ, isolated plaque-derived human myofibroblasts eds. Campbell's urology. 7th edition. Philadelphia: WB Saun- [47]. These further studies have the potential to 2 Noss MB, Day NS, Christ GJ, Melman A. The genetics and involved in PD. The study of apoptosis could immunology of Peyronie's disease. Int J Impot Res 2000;4:S127–390.
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Corresponding Author: Carla Loreto, MD, Depart-
13 Huppertz B, Kaufmann HGFP. The apoptosis cascade- ment of Anatomy, Diagnostic Pathology, Forensic morphological and immunohistochemical methods for its Medicine, Hygiene and Public Health, University of visualization. Anat Embryol 1999;200:1–18.
Catania, Via S. Sofia, 87-95123, Catania 95123, Italy.
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Statement of Authorship
16 Egydio PH, Sansalone S. Peyronie's reconstruction for maximum length and girth gain: Geometrical principles. Adv Category 1 Urol 2008;2008:205739 (Epub 2008).
(a) Conception and Design
17 Nesbit RM. Congenital curvature of the phallus: Report of Carla Loreto; Salvatore Sansalone three cases with description of corrective operation. J Urol (b) Acquisition of Data
18 Bradford MM. A rapid and sensitive method for the quan- Giuseppe Musumeci; Roberto Miano titation of microgram quantities of protein utilizing the (c) Analysis and Interpretation of Data
principle of protein-dye binding. Anal Biochem 1976;72: Maria Luisa Carnazza; Giuseppe Vespasiani 19 Somers KD, Dawson DM. Fibrin deposition in Peyronie's Category 2 disease plaque. J Urol 1997;157:306–16.
20 Shindel AW, Lin G, Ning H, Banie L, Huang YC, Lin G, Lin (a) Drafting the Article
CS, Lue FL. Pentoxifylline attenuates transforming growth Carla Loreto; Salvatore Sansalone factor-ß1-stimulated collagen deposition and elastogenesis in J Sex Med **;**:**–** Apoptosis in Peyronie's Disease human tunica albuginea-derived fibroblasts part 1: Impact on 35 Hasel C, Durr S, Rau B, Strater J, Schmid RM, Walczak H, extracellular matrix. J Sex Med 2010;7:1787–97.
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J Sex Med **;**:**–**

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