Lucattelli Monica, Lunghi Benedetta, Fineschi Silvia, Mirone Vincenzo, d'Emmanuele di Villa Bianca Roberta, Longo Nicola, Imbimbo Ciro, De Palma Raffaele, Sorrentino Raffaella, Lungarella Giuseppe, Cirino Giuseppe
Dipartimento di Fisiopatologia, Medicina Sperimentale e Sanità Pubblica, Università di Siena, Italy.
Int J Biochem Cell Biol. 2008;40(11):2638-48. doi: 10.1016/j.biocel.2008.05.012. Epub 2008 May 28.
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.
佩罗尼氏病（PD）的特征是白膜下出现炎症反应，成纤维细胞增殖形成增厚的纤维斑块，可导致疼痛、阴茎弯曲和勃起功能障碍。PD斑块的进展最终可能导致钙化或骨化。由于对疾病机制的了解有限，目前的治疗效果往往不尽人意。缺乏普遍接受的动物模型阻碍了研究进展。我们描述了一种紧密皮肤（Tsk）小鼠自发性PD的动物模型，Tsk小鼠是C57Bl/6J亚系，随着年龄增长会重现人类疾病的重要特征（纤维斑块形成、阴茎弯曲以及软骨样化生伴异位骨化区域）。组织学分析显示白膜结构明显紊乱，I型胶原蛋白过度积累。12月龄时，Tsk小鼠阴茎的特征为有软骨样化生和异位骨化区域的纤维斑块。缺氧诱导因子-1（HIF-1）的上调导致HIF-1靶基因（如TGFβ和诱导型一氧化氮合酶）的下游表达增加。这些因子与一些血小板衍生生长因子（PDGF）家族成员一起，可导致Tsk小鼠阴茎中的胶原蛋白沉积。它们还可影响软骨细胞分化和异位骨形成。总之，缺氧、HIF-1和HIF-1靶基因似乎在Tsk小鼠PD的发病机制中起重要作用。这种小鼠模型是实验室动物中自然发生的PD模型的首个实例，可能有助于识别对PD至关重要的信号通路，并应有助于新治疗干预措施的设计和测试。
