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Phosphodiesterase type 5 inhibitors (PDE5is) and selective estrogen receptor modulators (SERMs) can prevent the formation of fibrosis in in vitro and in vivo models of PD. However, it is unknown whether these drugs can also reverse established fibrosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>To investigate whether PDE5is and SERMs can reverse transforming growth factor beta 1 (TGF-\u03b21)\u2013induced myofibroblast transformation and determine the point of no return.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In-Cell enzyme-linked immunosorbent assay was used to quantify TGF-\u03b21\u2013induced myofibroblast transformation of human primary fibroblasts isolated from tunica albuginea (TA) of patients undergoing surgery for treatment of PD. Extracellular matrix production and collagen contraction assays were used as secondary assays. Reverse transcription\u2013quantitative polymerase chain reaction and In-Cell enzyme-linked immunosorbent assay were used to measure drug target expression. PDE5i (vardenafil) and SERM (tamoxifen) were applied at various time points after TGF-\u03b21.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Outcomes<\/jats:title>\n                    <jats:p>Reversibility of myofibroblast transformation and drug target expression were investigated in a time-dependent manner in TA-derived fibroblasts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Vardenafil or tamoxifen could not reverse the myofibroblast traits of alpha-smooth muscle actin expression and extracellular matrix production, whereas only tamoxifen affected collagen contraction after 72 hours of TGF-\u03b21 treatment. Phosphodiesterase 5A and estrogen receptor (ER)-\u03b2 were downregulated after 72 hours, and estrogen receptor -\u03b1 protein could not be quantified. Tamoxifen could prevent myofibroblast transformation until 36 hours after TGF-\u03b21 treatment, whereas vardenafil could prevent only 24 hours after TGF-\u03b21 treatment. This was mirrored by downregulation of drug targets on mRNA and protein level. Furthermore, antifibrotic signaling pathways, peroxisome proliferator-activated receptor gamma and betaglycan (TGFB receptor III), were significantly downregulated after 36 hours of TGF-\u03b21 exposure, as opposed to upregulation of profibrotic thrombospondin-1 at the same time point.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Translation<\/jats:title>\n                    <jats:p>This study suggests that using PDE5is and SERMs might only help for early-phase PD and further highlights the need to test drugs at the appropriate stage of the disease based on their mechanism of action.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Strengths &amp; Limitations<\/jats:title>\n                    <jats:p>The study uses primary human TA-derived fibroblasts that enhances translatability of the results. Limitations include that only 1 example of PDE5i- and SERM-type drug was tested. Time course experiments were only performed for marker expression experiments and not for functional assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This is the first study to demonstrate that timing for administration of drugs affecting myofibroblast transformation appears to be vital in in vitro models of PD, where 36 hours of TGF-\u03b21 treatment can be suggested as a \u201cpoint of no return\u201d for myofibroblast transformation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1016\/j.jsxm.2020.06.022","type":"journal-article","created":{"date-parts":[[2020,8,5]],"date-time":"2020-08-05T08:10:43Z","timestamp":1596615043000},"page":"1848-1864","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":24,"title":["Phosphodiesterase Type 5 Inhibitors and Selective Estrogen Receptor Modulators Can Prevent But Not Reverse Myofibroblast Transformation in Peyronie's Disease"],"prefix":"10.1093","volume":"17","author":[{"given":"Marcus M.","family":"Ilg","sequence":"first","affiliation":[{"name":"Medical Technology Research Centre , Chelmsford, Essex , UK"},{"name":"Anglia Ruskin University , Chelmsford, Essex , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon J.","family":"Stafford","sequence":"additional","affiliation":[{"name":"Medical Technology Research Centre , Chelmsford, Essex , UK"},{"name":"Anglia Ruskin University , Chelmsford, Essex , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Mateus","sequence":"additional","affiliation":[{"name":"Medical Technology Research Centre , Chelmsford, Essex , UK"},{"name":"Anglia Ruskin University , Chelmsford, Essex , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen A.","family":"Bustin","sequence":"additional","affiliation":[{"name":"Medical Technology 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