Antifibrotic effects of 2-carba cyclic phosphatidic acid (2ccPA) in systemic sclerosis: contribution to the novel treatment

Abstract

Background 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. Methods We 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. Results 2ccPA 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. Conclusions Our 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.

A 24‐Week, Phase IIa, Randomized, Double‐Blind, Placebo‐Controlled Study of Ziritaxestat in Early Diffuse Cutaneous Systemic Sclerosis

“…In human plasma, LPA C18:2 is the most common species, containing a fatty acid side chain of 18 carbon atoms, including 2 unsaturated bonds (14,15). In vitro and clinical studies have demonstrated that targeting the autotaxin/LPA pathway could modulate skin pathology in SSc (10,12,16,17). Ziritaxestat (GLPG1690), a small-molecule, selective autotaxin inhibitor with a novel mechanism of action, has been trialed for the treatment of idiopathic pulmonary fibrosis (IPF) (14,(18)(19)(20)(21) and SSc.…”

Lipid Alterations in Systemic Sclerosis

“…Another proposed molecule was 2-carba cyclic phosphatidic acid (2ccPA) (Ki16425, selective antagonist for LPA1 and LPA3 receptors) and cyclic phosphatidic acid. Their administration to the bleomycin-induced scleroderma mouse model caused regression of skin and pulmonary fibrosis ( Ohashi and Yamamoto, 2015 ; Higuchi et al, 2019 ).…”

Changes in Plasma Phospholipid Metabolism Are Associated with Clinical Manifestations of Systemic Sclerosis

“…Moreover, significantly higher serum levels of phospholipids like arachidonoyl (20:4)-Lysophosphatidic acid (LPA), and sphingosine 1-phosphate (S1P) in SSc versus controls were reported [12]. In LPA1 knockout mice, skin fibrosis was reduced in the bleomycin-induced scleroderma model [13][14][15]. Moreover, SSc patients' altered fatty acid profile in plasma and dendritic cells was reported [16].…”