Abstract
BackgroundCyclic phosphatidic acid (cPA) has an inhibitory effect on the autotaxin (ATX)/lysophosphatidic acid (LPA) axis, which has been implicated to play an important role in the progression of fibrosis in systemic sclerosis (SSc). The purpose of this study is to assess the antifibrotic activity of cPA for the treatment of SSc using SSc skin fibroblasts and an animal model of bleomycin-induced skin fibrosis.MethodsWe used a chemically stable derivative of cPA (2ccPA). First, we investigated the effect of 2ccPA on extracellular matrix (ECM) expression in skin fibroblasts. Next, the effect of 2ccPA on the intracellular cAMP levels was determined to investigate the mechanisms of the antifibrotic activity of 2ccPA. Finally, we administered 2ccPA to bleomycin-induced SSc model mice to evaluate whether 2ccPA prevented the progression of skin fibrosis.Results2ccPA decreased ECM expression in SSc skin fibroblasts and TGF-β1-treated healthy skin fibroblasts without LPA stimulation. 2ccPA increased the intracellular cAMP levels in skin fibroblasts, suggesting that the antifibrotic effect of 2ccPA was the consequence of the increase in the intracellular cAMP levels. Administration of 2ccPA also ameliorated the progression of bleomycin-induced skin fibrosis in mice.ConclusionsOur data indicated that 2ccPA had inhibitory effects on the progression of skin fibrosis by abrogating ECM production from activated skin fibroblasts. These cells were repressed, at least in part, by increased intracellular cAMP levels. 2ccPA may be able to be used to treat fibrotic lesions in SSc.
Highlights
Cyclic phosphatidic acid has an inhibitory effect on the autotaxin (ATX)/lysophosphatidic acid (LPA) axis, which has been implicated to play an important role in the progression of fibrosis in systemic sclerosis (SSc)
The skin thickness in the areas of Discussion we demonstrated the antifibrotic effect of 2-carba derivative of Cyclic phosphatidic acid (cPA) (2ccPA) on skin fibrosis. 2ccPA decreased the expression levels of LPA-driven Connective tissue growth factor (CTGF) and IL-6 mRNAs in skin fibroblasts
We found that 2ccPA had direct effects on SSc skin fibroblasts to diminish the production of extracellular matrix (ECM) molecules and on normal skin fibroblasts stimulated with TGF-β1. 2ccPA elevated the levels of the antifibrogenic factors Hepatocyte growth factor (HGF) and prostaglandin E2 (PGE2) in the culture medium of SSc skin fibroblasts
Summary
Cyclic phosphatidic acid (cPA) has an inhibitory effect on the autotaxin (ATX)/lysophosphatidic acid (LPA) axis, which has been implicated to play an important role in the progression of fibrosis in systemic sclerosis (SSc). The purpose of this study is to assess the antifibrotic activity of cPA for the treatment of SSc using SSc skin fibroblasts and an animal model of bleomycin-induced skin fibrosis. LPA is known to regulate several cellular properties, Higuchi et al Arthritis Research & Therapy (2019) 21:103 including survival, proliferation, differentiation, and motility [8,9,10]. These physiological features have been implicated in the pathogenesis of conditions such as autoimmunity, fibrosis, cancer, and inflammation; LPA has been identified as a therapeutic target in various intractable diseases [11, 12]. LPA1 knockout mice showed less extensive skin fibrosis in bleomycin-induced skin fibrosis [16]
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