title: A new mouse model of Peyronie's disease: an increased expression of hypoxia-inducible factor-1 target genes during the development of penile changes.
abstract: Peyronie's disease (PD) is characterized by an inflammatory response beneath the tunica albuginea with fibroblast proliferation forming a thickened fibrous plaque that may cause pain, penile curvature and erectile dysfunction. The progression of the PD plaque may eventually lead to calcification or ossification. Current therapeutic success is often unsatisfactory because of limited insight into disease mechanisms. Research has been hampered by the lack of a universally accepted animal model. We describe an animal model of spontaneous PD in tight skin (Tsk) mice, a C57Bl/6J subline that reproduces with age important features of the human disease (fibrous plaque formation, penile bending and areas of chondroid metaplasia with heterotopic ossification). Histological analysis demonstrated an evident structural disorganization of the tunica albuginea with excessive accumulation of type I collagen. At 12 months of age, fibrous plaques with areas of chondroid metaplasia and heterotopic ossification characterized Tsk penises. The up-regulation of hypoxia-inducible factor-1 (HIF-1) leads to an increased downstream expression of HIF-1 target genes, such as TGFbeta and iNOS. These factors, together with some PDGF family members, can cause collagen deposition in Tsk penises. They can also influence chondrocyte differentiation and heterotopic bone formation. In conclusion, hypoxia, HIF-1 and HIF-1 target genes appear to play an important role in the pathogenesis of PD in Tsk mice. This mouse model that is the first example of naturally occurring model of PD in laboratory animals may aid in the identification of signalling pathways crucial for PD and should facilitate the designing and testing of new therapeutic interventions.
authors.affiliation: Dipartimento di Fisiopatologia, Medicina Sperimentale e Sanità Pubblica, Università di Siena, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Lucattelli
authors.forename: Benedetta
authors.initials: B
authors.lastname: Lunghi
authors.forename: Silvia
authors.initials: S
authors.lastname: Fineschi
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mirone
authors.forename: Roberta
authors.initials: R
authors.lastname: d'Emmanuele di Villa Bianca
authors.forename: Nicola
authors.initials: N
authors.lastname: Longo
authors.forename: Ciro
authors.initials: C
authors.lastname: Imbimbo
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Palma
authors.forename: Raffaella
authors.initials: R
authors.lastname: Sorrentino
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lungarella
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cirino
mesh_terms: D000818:Animals; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010411:Penile Induration / Q000235:genetics / Q000473:pathology; D010413:Penis / Q000033:anatomy & histology / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D024043:Collagen Type II; D051793:Hypoxia-Inducible Factor 1; D016212:Transforming Growth Factor beta; D052247:Nitric Oxide Synthase Type II