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Cited by 238Dupuytren's Contracture and TreatmentsUrological Disorders and TreatmentsSexual function and dysfunction studies

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The Role of Intrinsic Pathway in Apoptosis Activation and Progression in Peyronie’s Disease

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Loreto, Carla, La Rocca, Giampiero, Anzalone, Rita, Caltabiano, Rosario, Vespasiani, Giuseppe, Castorina, Sergio, Ralph, David J., Cellek, Selim, Musumeci, Giuseppe, Giunta, Salvatore, Djinovic, Rados, Basic, Dragoslav, Sansalone, Salvatore·2014·BioMed Research International
DOI 10.1155/2014/616149PMC PMC4147380
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Abstract

Peyronie’s disease (PD) is characterized with formation of fibrous plaques which result in penile deformity, pain, and erectile dysfunction. The aim of this study was to investigate the activation of the intrinsic apoptotic pathway in plaques from PD patients. Tunica albuginea from either PD or control patients was assessed for the expression of bax, bcl-2 and caspases 9 and 3 using immunohistochemistry and by measurement of apoptotic cells using TUNEL assay. Bax overexpression was observed in metaplastic bone tissue, in fibroblasts, and in myofibroblast of plaques from PD patients. Little or no bcl-2 immunostaining was detected in samples from either patients or controls. Caspase 3 immunostaining was very strong in fibrous tissue, in metaplasic bone osteocytes, and in primary ossification center osteoblasts. Moderate caspase 9 immunostaining was seen in fibrous cells plaques and in osteocytes and osteoblasts of primary ossification centers from PD patients. Control samples were negative for caspase 9 immunostaining. In PD patients the TUNEL immunoassay showed intense immunostaining of fibroblasts and myofibroblasts, the absence of apoptotic cells in metaplasic bone tissue and on the border between fibrous and metaplastic bone tissue. Apoptosis occurs in stabilized PD plaques and is partly induced by the intrinsic pathway.

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Figures

Figure 1 Apoptosis works through two main, alternative pathways: death receptor-mediated (or extrinsic) and mitochondria-dependent (or intrinsic). The former pathway is initiated by ligation of specific death receptors by their ligands. The main death receptors—Fas and tumour necrosis factor- (TNF-) related apoptosis inducing ligand (TRAIL) receptors DR4 and DR5—induce cell death following ligation with Fas ligand (FasL) or TRAIL, respectively, followed by recruitment of procaspase 8. This process gives rise to caspase 8 activation. The latter induces apoptosis by directly activating caspase 3 or by cleaving bid (BH3 interacting domain death agonist), resulting in mitochondrial dysfunction and subsequent release of cytochrome C and activation of caspases 9 and 3. Caspase 3 promotes the typical apoptosis features, including DNA fragmentation and cell death in several tissues. The mitochondrial pathway is partly influenced by bcl family members bound to the mitochondrial membrane, including bax and bcl-2, which are, respectively, pro- or antiapoptotic regulatory proteins. The antiapoptotic proteins bcl-2 and bcl-XL inhibit cytochrome c release, whereas bcl-2—associated X protein(bax), bcl-2 homologous antagonist/killer (bak), and bid, all proapoptotic proteins, promote its release from mitochondria. Cytochrome C and deoxyadenosine triphosphate (dATP) bind to apoptotic protease activating factor (APAF-1) to form a multimeric complex that recruits and activates procaspase 9, an apoptosis-mediating executioner protease that in turn activates caspase 3, resulting in cell apoptosis.
Figure 1 Apoptosis works through two main, alternative pathways: death receptor-mediated (or extrinsic) and mitochondria-dependent (or intrinsic). The former pathway is initiated by ligation of specific death receptors by their ligands. The main death receptors—Fas and tumour necrosis factor- (TNF-) related apoptosis inducing ligand (TRAIL) receptors DR4 and DR5—induce cell death following ligation with Fas ligand (FasL) or TRAIL, respectively, followed by recruitment of procaspase 8. This process gives rise to caspase 8 activation. The latter induces apoptosis by directly activating caspase 3 or by cleaving bid (BH3 interacting domain death agonist), resulting in mitochondrial dysfunction and subsequent release of cytochrome C and activation of caspases 9 and 3. Caspase 3 promotes the typical apoptosis features, including DNA fragmentation and cell death in several tissues. The mitochondrial pathway is partly influenced by bcl family members bound to the mitochondrial membrane, including bax and bcl-2, which are, respectively, pro- or antiapoptotic regulatory proteins. The antiapoptotic proteins bcl-2 and bcl-XL inhibit cytochrome c release, whereas bcl-2—associated X protein(bax), bcl-2 homologous antagonist/killer (bak), and bid, all proapoptotic proteins, promote its release from mitochondria. Cytochrome C and deoxyadenosine triphosphate (dATP) bind to apoptotic protease activating factor (APAF-1) to form a multimeric complex that recruits and activates procaspase 9, an apoptosis-mediating executioner protease that in turn activates caspase 3, resulting in cell apoptosis.CC BY · PubMed Central
Figure 2 Bax immunostaining in plaque from a patient with Peyronie's disease (a, b, c) and in control tissue (d); magnification is 20x for all. Scale bar = 100 μm. Asterisk at (a): areas of osseous metaplasia with heterotopic ossification; double arrowhead: an osteocyte in bone lacunae; arrow: bax overexpression in an osteoblast of a primary ossification center. Arrow at (b): bax overexpression in an osteocyte in metaplastic bone; double arrowhead: bax overexpression in osteoblasts and fibroblasts on the border of the metaplastic bone tissue; asterisk: bax overexpression in a blood vessel.
Figure 2 Bax immunostaining in plaque from a patient with Peyronie's disease (a, b, c) and in control tissue (d); magnification is 20x for all. Scale bar = 100 μm. Asterisk at (a): areas of osseous metaplasia with heterotopic ossification; double arrowhead: an osteocyte in bone lacunae; arrow: bax overexpression in an osteoblast of a primary ossification center. Arrow at (b): bax overexpression in an osteocyte in metaplastic bone; double arrowhead: bax overexpression in osteoblasts and fibroblasts on the border of the metaplastic bone tissue; asterisk: bax overexpression in a blood vessel.CC BY · PubMed Central
Figure 3 Bcl-2 immunostaining in plaque from a patient with Peyronie's disease (a) and in control tissue (b); magnification is 20x for all. Scale bar = 100 μm.
Figure 3 Bcl-2 immunostaining in plaque from a patient with Peyronie's disease (a) and in control tissue (b); magnification is 20x for all. Scale bar = 100 μm.CC BY · PubMed Central
Figure 4 Caspase 3 immunostaining in plaque from a patient with Peyronie's disease ((a) and (b)) and in control tissue (c); magnification is 20x for all. Scale bar = 100 μm. (a) Arrowheads: caspase 3 immunostaining in fibrous tissue; arrow: caspase 3 immunostaining in a metaplastic bone osteocyte. (b) Arrows: haversian canals; arrowhead: a primary ossification center.
Figure 4 Caspase 3 immunostaining in plaque from a patient with Peyronie's disease ((a) and (b)) and in control tissue (c); magnification is 20x for all. Scale bar = 100 μm. (a) Arrowheads: caspase 3 immunostaining in fibrous tissue; arrow: caspase 3 immunostaining in a metaplastic bone osteocyte. (b) Arrows: haversian canals; arrowhead: a primary ossification center.CC BY · PubMed Central
Figure 5 Caspase 9 immunostaining in plaque from a patient with Peyronie's disease (a and b) and in control tissue (c); magnification is 20x for all. Scale bar = 100 μm. (a) Arrows: caspase 9 immunostaining in fibrous cells from PD plaques (Figure 5(a), arrows) and in osteocytes (arrow). (b) Arrowheads: caspase 9 immunostaining in osteoblasts of a primary ossification centers.
Figure 5 Caspase 9 immunostaining in plaque from a patient with Peyronie's disease (a and b) and in control tissue (c); magnification is 20x for all. Scale bar = 100 μm. (a) Arrows: caspase 9 immunostaining in fibrous cells from PD plaques (Figure 5(a), arrows) and in osteocytes (arrow). (b) Arrowheads: caspase 9 immunostaining in osteoblasts of a primary ossification centers.CC BY · PubMed Central
Figure 6 TUNEL staining in plaque from a patient with Peyronie's disease ((a) and (b)) and in control tissue (c); magnification is 20x for all. Scale bar = 100 μm.
Figure 6 TUNEL staining in plaque from a patient with Peyronie's disease ((a) and (b)) and in control tissue (c); magnification is 20x for all. Scale bar = 100 μm.CC BY · PubMed Central
Figure 7 Quantitative analysis of bax (a), bcl-2 (b), caspase 3 (c), and caspase 9 (d) immunostaining in PD samples. In both panels, asterisks indicate significant differences versus the control group (P < 0.05).
Figure 7 Quantitative analysis of bax (a), bcl-2 (b), caspase 3 (c), and caspase 9 (d) immunostaining in PD samples. In both panels, asterisks indicate significant differences versus the control group (P < 0.05).CC BY · PubMed Central
Figure 8 Quantitative analysis of TUNEL-positive cell staining in PD samples. Different cell positivity can be seen in areas with osseous metaplasia and in fibrous tissue areas. Asterisks indicate significant differences versus the control group (P < 0.01).
Figure 8 Quantitative analysis of TUNEL-positive cell staining in PD samples. Different cell positivity can be seen in areas with osseous metaplasia and in fibrous tissue areas. Asterisks indicate significant differences versus the control group (P < 0.01).CC BY · PubMed Central

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Research works printed but not linked: 7

  1. 10.1016/S0094-0143(05)70146-4 · DOI
  2. 2012, Advances in Clinical and Experimental Medicine, 21, 607
  3. 2012, Sinaling pathway that regulate life and cell death: evolution of apoptosis in the contex of self-defence, 124
  4. 10.1038/aja.2012.9 · DOI
  5. 1992, Blood, 80, 879, 10.1182/blood.V80.4.879.879 · DOI
  6. 10.1016/S0022-5347(01)65360-6 · DOI
  7. 10.1095/biolreprod64.3.974 · DOI

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Metadata

Authors
Loreto, C., La Rocca, G., Anzalone, R., Caltabiano, R., Vespasiani, G., Castorina, S., Ralph, D. J., Cellek, S., Musumeci, G., Giunta, S., Djinovic, R., Basic, D., & Sansalone, S.
Affiliations
  • University of Catania (IT)
  • Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, 90100 Palermo, Italy
  • University of Palermo (IT)
  • University of Rome Tor Vergata (IT)
  • University College Hospital (GB)
  • Cranfield University (GB)
  • Sava Perovic Foundation, Center for Genito-Urinary Reconstructive Surgery, 11000 Belgrade, Serbia
  • Clinic of Urology, Clinical Center Nis, 18000 Nis, Serbia
Corresponding author
Loreto, Carla
ORCID
Venue
BioMed Research International
Publisher
Wiley
Published
2014
Volume
2014
Pages
1-10
ISSN
  • 1110-7243 (ISSN-L)
  • 2314-6133
  • 2314-6141
DOI
10.1155/2014/616149
PMC
PMC4147380
OpenAlex
W1973666710
Cited by
108
References
48
Citations by year
2026: 1 · 2025: 6 · 2024: 4 · 2023: 14 · 2022: 20 · 2021: 22 · 2020: 15 · 2019: 12 · 2018: 4 · 2017: 3 · 2016: 5 · 2015: 2
FWCI
2.77
Type
journal article
Language
en
Open access
Licence
Locations
  • BioMed Research International (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Rheumatology › Dupuytren's Contracture and Treatments
  • Health Sciences › Medicine › Urology › Urological Disorders and Treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Sexual function and dysfunction studies
Keywords
Peyronie's disease, mitochondrial apoptosis, apoptosis, tunica albuginea, fibrous plaque, Bax, Bcl-2, caspase-3, caspase-9, myofibroblasts, fibroblasts, ossification centers, penile deformity
MeSH terms
Adult, Aged, Humans, Male, Middle Aged, Penile Induration, Staining and Labeling, Signal Transduction, Apoptosis, Disease Progression, In Situ Nick-End Labeling, bcl-2-Associated X Protein, Caspase 3, Caspase 9, Young Adult

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