Mähönen Katariina, Mogollon Isabel, Hassinen Antti, Polso Minttu, Välimäki Katja, Potdar Swapnil, Chowdhury Al-Amin, Ranki Annamari, Saarela Jani, Pietiäinen Vilja, Panelius Jaana
epartment of Dermatology and Allergology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Institute for Molecular Medicine Finland - FIMM, Helsinki Institute for Life Sciences - HiLIFE, University of Helsinki, Helsinki, Finland.
Acta Derm Venereol. 2025 Aug 3;105:adv43088. doi: 10.2340/actadv.v105.43088.
Localized scleroderma is a rare autoimmune disease characterized by progressive fibrosis of the skin and its underlying structures, causing loss of normal tissue structure and function. Myofibroblasts, differentiated from fibroblasts by high expression of α-smooth muscle actin, play a key role in the pathogenesis with continuous production of collagen and other extracellular matrix components. Transforming growth factor β promotes myofibroblast transformation and is central to the pathogenesis of fibrotic diseases. Targeted therapies for skin fibrosis are lacking, and current treatment consisting of topical steroids and immunosuppressive drugs often has limited efficacy. In this study, testing was performed with 78 drugs on lesional localized scleroderma fibroblasts to find potential new therapies, with α-smooth muscle actin and collagen-1 expression as markers for antifibrotic effect. Several drugs belonging to inhibitors of tyrosine kinase, phosphoinositide-3 kinase, and transforming growth factor β receptor were found to have an antifibrotic effect in localized scleroderma fibroblasts. Along with increased expression of transforming growth factor β1, Smad3, and AKT found in lesional localized scleroderma skin, these results confirm transforming growth factor β pathway as a treatment target. Additionally, androgen receptor antagonists showed potential antifibrotic effects, co-aligning with an increased expression of androgen receptor in localized scleroderma skin.
局限性硬皮病是一种罕见的自身免疫性疾病，其特征是皮肤及其下方结构进行性纤维化，导致正常组织结构和功能丧失。肌成纤维细胞由成纤维细胞通过高表达α-平滑肌肌动蛋白分化而来，在发病机制中起关键作用，持续产生胶原蛋白和其他细胞外基质成分。转化生长因子β促进肌成纤维细胞转化，是纤维化疾病发病机制的核心。目前缺乏针对皮肤纤维化的靶向治疗方法，而目前由局部类固醇和免疫抑制药物组成的治疗通常疗效有限。在本研究中，对78种药物进行了测试，以寻找针对局限性硬皮病成纤维细胞的潜在新疗法，以α-平滑肌肌动蛋白和胶原蛋白-1表达作为抗纤维化作用的标志物。发现几种属于酪氨酸激酶、磷酸肌醇-3激酶和转化生长因子β受体抑制剂的药物在局限性硬皮病成纤维细胞中具有抗纤维化作用。随着局限性硬皮病病变皮肤中转化生长因子β1、Smad3和AKT表达的增加，这些结果证实转化生长因子β通路是一个治疗靶点。此外，雄激素受体拮抗剂显示出潜在的抗纤维化作用，这与局限性硬皮病皮肤中雄激素受体表达增加相一致。
