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Dipeptidylpeptidase 4 as a Marker of Activated Fibroblasts and a Potential Target for the Treatment of Fibrosis in Systemic Sclerosis
Author(s) -
Soare Alina,
Györfi Hermina A.,
Matei Alexandru E.,
Dees Clara,
Rauber Simon,
Wohlfahrt Thomas,
Chen ChihWei,
Ludolph Ingo,
Horch Raymund E.,
Bäuerle Tobias,
Hörsten Stephan,
Mihai Carina,
Distler Oliver,
Ramming Andreas,
Schett Georg,
Distler Jörg H. W.
Publication year - 2020
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41058
Subject(s) - myofibroblast , fibroblast , fibrosis , dipeptidyl peptidase 4 , wound healing , bleomycin , western blot , vildagliptin , pulmonary fibrosis , medicine , chemistry , cancer research , pathology , endocrinology , immunology , diabetes mellitus , type 2 diabetes , biochemistry , chemotherapy , in vitro , gene
Objective Expression of dipeptidylpeptidase 4 ( DPP ‐4) identifies a dermal fibroblast lineage involved in scarring during wound healing. The role of DDP ‐4 in tissue fibrosis is, however, unknown. The aim of the present study was to evaluate DPP ‐4 as a potential target for the treatment of fibrosis in patients with systemic sclerosis ( SS c). Methods Expression of DPP ‐4 in skin biopsy samples and dermal fibroblasts was analyzed by real‐time polymerase chain reaction, immunofluorescence, and Western blot analyses. The activity of DPP ‐4 was modulated by overexpression, knockdown, and pharmacologic inhibition of DPP 4 using sitagliptin and vildagliptin. The effects of DPP 4 inhibition were analyzed in human dermal fibroblasts and in different mouse models of SS c (each n = 6). Results The expression of DPP ‐4 and the number of DPP ‐4–positive fibroblasts were increased in the fibrotic skin of SS c patients, in a transforming growth factor β ( TGF β)–dependent manner. DPP ‐4–positive fibroblasts expressed higher levels of myofibroblast markers and collagen (each P < 0.001 versus healthy controls). Overexpression of DPP 4 promoted fibroblast activation, whereas pharmacologic inhibition or genetic inactivation of DPP 4 reduced the proliferation, migration, and expression of contractile proteins and release of collagen (each P < 0.001 versus control mice) by interfering with TGF β‐induced ERK signaling. DPP 4‐knockout mice were less sensitive to bleomycin‐induced dermal and pulmonary fibrosis ( P < 0.0001 versus wild‐type controls). Treatment with DPP 4 inhibitors promoted regression of fibrosis in mice that had received bleomycin challenge and mice with chronic graft‐versus‐host disease, and ameliorated fibrosis in TSK 1 mice (each P < 0.001 versus untreated controls). These antifibrotic effects were associated with a reduction in inflammation. Conclusion DPP ‐4 characterizes a population of activated fibroblasts and shows that DPP ‐4 regulates TGF β‐induced fibroblast activation in the fibrotic skin of SS c patients. Inhibition of DPP 4 exerts potent antifibrotic effects when administered in well‐tolerated doses. As DPP 4 inhibitors are already in clinical use for diabetes, these results may have direct translational implications for the treatment of fibrosis in patients with SS c.