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Unveiling the Molecular Hallmarks of Peyronie's Disease: A Comprehensive Narrative Review - Beyond the Abstract

Fibrosis represents a pivotal step in the process of tissue restoration during wound healing, yet dysregulation at the molecular level can lead to pathological fibrosis.1 While fibrotic diseases can manifest systemically (such as systemic sclerosis), they typically exhibit tissue-specific patterns (as seen in idiopathic pulmonary fibrosis).2 Among urogenital fibrotic disorders in males, Peyronie's disease is one of the most commonly encountered pathologies.3 The prevalence rate of Peyronie's disease ranges from 0.4% to 20.3%, with significant implications for erectile dysfunction, penile deformity, and pain.4

One of the most extensively studied proteins in the molecular pathophysiology of Peyronie's disease is transforming growth factor-beta (TGF-β), responsible for the activation of fibroblasts.5,6 Additionally, TGF-β regulates the expression of extracellular matrix proteins that form the backbone of fibrotic plaques through the suppressor of mothers against decapentaplegic (SMAD) signaling proteins.6 Another growth factor implicated in the pathophysiology of Peyronie's disease is platelet-derived growth factor (PDGF) along with fibroblast growth factor (FGF).7,8 Matrix metalloproteinases (MMP) enzymes play a crucial role in the breakdown of the extracellular matrix, including collagen and elastin.9 Decreased activity of these enzymes results in collagen accumulation.9,10 Tissue inhibitors of metalloproteinases (TIMP) proteins are responsible for inhibiting MMP enzymes, thereby preventing excessive collagen accumulation or extracellular matrix degradation.11,12 In Peyronie's disease, an imbalance between MMP and TIMP proteins is observed, with an increase in TIMP levels and a decrease in MMP enzyme levels.13

While numerous interventional and non-interventional treatment options are available for Peyronie's disease management, direct therapeutic interventions targeting fibrosis biology remain scarce.4 A clearer understanding of the molecular pathophysiology of Peyronie's disease may pave the way for more conservative approaches in the future. For instance, in idiopathic pulmonary fibrosis, antifibrotic pharmacological agents such as nintedanib (a tyrosine kinase inhibitor), pirfenidone (a SMAD3 phosphorylation inhibitor), and fresolimumab (a monoclonal antibody capable of inhibiting all TGF isoforms) have been utilized.14 Additionally, in cardiac fibrosis, fibroblast activation protein (FAP)-targeted chimeric antigen receptor T (CAR-T) cells have been employed, demonstrating reduced cardiac scarring and increased ejection fraction.15 In our recent publication in the Journal of Medical Hypotheses, we discussed the potential use of FAP-targeted CAR-T cells in Peyronie's disease.16 By providing a molecular guide, our paper aims to assist clinicians and researchers involved in Peyronie's disease research.13 We hope this serves as a valuable resource for further exploration in this field.

Commentary by: Murat Gül, MD, FEBU, Associate Professor, Department of Urology, Selcuk University School of Medicine, Konya, Turkey

Written by: Ali Şahin,1 Murat Gül2

  1. Selcuk University School of Medicine, Konya, Turkey
  2. Department of Urology, Selcuk University School of Medicine, Konya, Turkey
References:

  1. Wynn T. Cellular and molecular mechanisms of fibrosis. The Journal of Pathology. 2008;214(2):199-210. doi:10.1002/path.2277
  2. Taroni JN, Greene CS, Martyanov V, et al. A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis. Genome Med. 2017;9(1):27. doi:10.1186/s13073-017-0417-1
  3. Rahardjo HE, Märker V, Tsikas D, Kuczyk MA, Ückert S, Bannowsky A. Fibrotic Diseases of the Human Urinary and Genital Tract: Current Understanding and Potential Strategies for Treatment. JCM. 2023;12(14):4770. doi:10.3390/jcm12144770
  4. Salonia A, Bettocchi C, Boeri L, et al. European Association of Urology Guidelines on Sexual and Reproductive Health—2021 Update: Male Sexual Dysfunction. European Urology. 2021;80(3):333-357. doi:10.1016/j.eururo.2021.06.007
  5. El-Sakka AI, Hassoba HM, Pillarisetty RJ, Dahiya R, Lue TF. Peyronie’s disease is associated with an increase in transforming growth factor-beta protein expression. J Urol. 1997;158(4):1391-1394.
  6. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-β family signaling. Nature. 2003;425(6958):577-584. doi:10.1038/nature02006
  7. Lucattelli M, Lunghi B, Fineschi S, et al. A new mouse model of Peyronie’s disease: An increased expression of hypoxia-inducible factor-1 target genes during the development of penile changes. The International Journal of Biochemistry & Cell Biology. 2008;40(11):2638-2648. doi:10.1016/j.biocel.2008.05.012
  8. Mulhall JP, Thom J, Lubrano T, Shankey TV. Basic fibroblast growth factor expression in Peyronie’s disease. J Urol. 2001;165(2):419-423. doi:10.1097/00005392-200102000-00016
  9. Visse R, Nagase H. Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases: Structure, Function, and Biochemistry. Circulation Research. 2003;92(8):827-839. doi:10.1161/01.RES.0000070112.80711.3D
  10. Page-McCaw A, Ewald AJ, Werb Z. Matrix metalloproteinases and the regulation of tissue remodeling. Nat Rev Mol Cell Biol. 2007;8(3):221-233. doi:10.1038/nrm2125
  11. Murphy G. Tissue inhibitors of metalloproteinases. Genome Biol. 2011;12(11):233. doi:10.1186/gb-2011-12-11-233
  12. Roeb E. Matrix metalloproteinases and liver fibrosis (translational aspects). Matrix Biol. 2018;68-69:463-473. doi:10.1016/j.matbio.2017.12.012
  13. Şahin A, Babayev H, Cirigliano L, et al. Unveiling the molecular Hallmarks of Peyronie’s disease: a comprehensive narrative review. Int J Impot Res. Published online March 7, 2024. doi:10.1038/s41443-024-00845-2
  14. Sgalla G, Flore M, Siciliano M, Richeldi L. Antibody-based therapies for idiopathic pulmonary fibrosis. Expert Opin Biol Ther. 2020;20(7):779-786. doi:10.1080/14712598.2020.1735346
  15. Aghajanian H, Kimura T, Rurik JG, et al. Targeting cardiac fibrosis with engineered T cells. Nature. 2019;573(7774):430-433. doi:10.1038/s41586-019-1546-z
  16. Şahin A, Babayev H, Gül M. FAP-targeted CAR T-cell therapy: A promising approach for the treatment of Peyronie’s disease. Medical Hypotheses. 2023;178:111130. doi:10.1016/j.mehy.2023.111130
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