Dipeptidyl-peptidase-4 as a marker of activated fibroblasts and a potential target for the treatment of fibrosis in Systemic Sclerosis

Abstract

BACKGROUND Dipeptidyl-peptidase-4 (DPP4) identifies a dermal fibroblast lineage involved in scaring during wound healing. The role of DDP4 in tissue fibrosis, however, is unknown. The aim of the present study was to evaluate DPP4 as a potential target for the treatment of fibrosis in systemic sclerosis (SSc). METHODS The expression of DPP4 was analyzed by real-time PCR, immunofluorescence and Western blot. The activity of DPP4 was modulated by overexpression, knockdown and pharmacological inhibition using Sitagliptin and Vildagliptin. The effects of DPP4 inhibition were analyzed in human dermal fibroblasts and in different mouse models of SSc (n=6). RESULTS The expression of DPP4 and the number of DPP4 positive fibroblasts were increased in fibrotic skin of SSc patients in a TGF-β dependent manner. DPP4 positive fibroblasts expressed higher levels of myofibroblast markers and collagen (p<0.001). Overexpression of DPP4 promoted fibroblast activation, whereas pharmacological or genetic inactivation of DPP4 reduced proliferation, migration, expression of contractile proteins and release of collagen by interfering with TGF-β-induced ERK signaling (p<0.001). DPP4-knockout mice were less sensitive to bleomycin-induced dermal and pulmonary fibrosis (p<0.0001). Treatment with DPP4 inhibitors promoted regression of fibrosis induced by bleomycin- or chronic graft-versus-host disease and ameliorated fibrosis in TSK1 mice (p<0.001). The antifibrotic effects were associated with reduced inflammation. CONCLUSION DPP4 characterizes a population of activated fibroblasts and regulates TGF-β-induced fibroblast activation. Inhibition of DPP4 exerts potent anti-fibrotic effects in well tolerated doses. These results may have direct translational implications as DPP4 inhibitors are already in clinical use for diabetes. This article is protected by copyright. All rights reserved