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Translational engagement of lysophosphatidic acid receptor 1 in skin fibrosis: from dermal fibroblasts of patients with scleroderma to tight skin 1 mouse
Author(s) -
Ledein Laetitia,
Léger Bertrand,
Dees Clara,
Beyer Christian,
Distler Alfiya,
Vettori Serena,
Boukaiba Rachid,
Bidouard Jean Pierre,
Schaefer Matthias,
Pernerstorfer Josef,
Ruetten Hartmut,
Jagerschmidt Alexandre,
Janiak Philip,
Distler Jörg H.W.,
Distler Oliver,
Illiano Stéphane
Publication year - 2020
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15190
Subject(s) - myofibroblast , lysophosphatidic acid , fibrosis , dermal fibroblast , inflammation , fibroblast , medicine , wnt signaling pathway , receptor , cancer research , pathology , biology , immunology , signal transduction , microbiology and biotechnology , cell culture , genetics
Background and Purpose Genetic deletion and pharmacological studies suggest a role for lysophosphatidic acid (LPA 1 ) receptor in fibrosis. We investigated the therapeutic potential in systemic sclerosis (SSc) of a new orally active selective LPA 1 receptor antagonist using dermal fibroblasts from patients and an animal model of skin fibrosis. Experimental Approach Dermal fibroblast and skin biopsies from systemic sclerosis patients were used. Myofibroblast differentiation, gene expression and cytokine secretion were measured following LPA and/or SAR100842 treatment. Pharmacolgical effect of SAR100842 was assessed in the tight skin 1 (Tsk1) mouse model. Key Results SAR100842 is equipotent against various LPA isoforms. Dermal fibroblasts and skin biopsies from patients with systemic sclerosis expressed high levels of LPA 1 receptor. The LPA functional response (Ca 2+ ) in systemic sclerosis dermal fibroblasts was fully antagonized with SAR100842. LPA induced myofibroblast differentiation in systemic sclerosis dermal and idiopathic pulmonary fibrosis lung fibroblasts and the secretion of inflammatory markers and activated Wnt markers. Results from systemic sclerosis dermal fibroblasts mirror those obtained in a mouse Tsk1 model of skin fibrosis. Using a therapeutic protocol, SAR100842 consistently reversed dermal thickening, inhibited myofibroblast differentiation and reduced skin collagen content. Inflammatory and Wnt pathway markers were also inhibited by SAR100842 in the skin of Tsk1 mice. Conclusion and Implications The effects of SAR100842 on LPA‐induced inflammation and on mechanisms linked to fibrosis like myofibroblast differentiation and Wnt pathway activation indicate that LPA 1 receptor activation plays a key role in skin fibrosis. Our results support the therapeutic potential of LPA 1 receptor antagonists in systemic sclerosis.