Radiation-induced morphea (RIM) is a rare entity of inflammatory skin fibrosis occurring in breast cancer patients after radiotherapy. Targeted treatment is absent because the knowledge about relevant pathomechanisms is limited. The inflammatory cytokine osteopontin (OPN) is an emerging driver of myofibroblast differentiation and fibrosis. Here, we study the role of OPN in RIM pathophysiology and investigate the antifibrotic effects of mesalazine as a novel treatment for RIM. We isolated primary skin fibroblasts from RIM and control patients for subsequent characterization by western blot, qPCR, IF, and ELISA. Compared to control, we found a strong myofibroblast phenotype in RIM reflected by increased expression of αSMA, reduced proliferation, and a striking upregulation of OPN. An ELISA of peripheral blood samples revealed significantly higher OPN concentrations in RIM (≈40ng/mL) patients, compared to healthy individuals (≈20ng/mL). Mechanistically, increased activity of the fibrotic β-Catenin-c-Myc pathway and higher levels of reactive oxygen species (ROS) were found to contribute to OPN overexpression and myofibroblast differentiation in RIM. Re-radiation of fibroblasts induced OPN, ROS, and myofibroblast marker genes. Mesalazine treatment prevented nuclear translocation of β-Catenin and c-Myc and reduced ROS expression thereby abolishing OPN expression and myofibroblast differentiation. Based on these findings, one RIM patient was treated with 2 g of oral mesalazine per day for 6 weeks leading to soothed inflammation, tissue softening, and reduction of pain. In conclusion, we identified up-regulation of the β-Catenin-c-Myc pathway, increased ROS-production, and excess OPN release as relevant disease drivers in RIM. Furthermore, we provide proof-of-concept for repurposing mesalazine to treat RIM in a well-tolerable and cost-effective manner.

ESDR359 - Anti-osteopontin treatment with mesalazine improves fibroblast dysfunction in radiation-induced morphea

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING