A Metabolically-Stabilized Phosphonate Analog of Lysophosphatidic Acid Attenuates Collagen-Induced Arthritis |
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| Authors: | Ioanna Nikitopoulou Eleanna Kaffe Ioanna Sevastou Ivi Sirioti Martina Samiotaki Damian Madan Glenn D Prestwich Vassilis Aidinis |
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| Institution: | 1. Institute of Immunology, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece.; 2. Echelon Biosciences Inc, Salt Lake City, Utah, United States of America.; 3. Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah, United States of America.; The University of Tennessee Health Science Center, United States of America, |
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| Abstract: | Rheumatoid arthritis (RA) is a destructive arthropathy with systemic manifestations, characterized by chronic synovial inflammation. Under the influence of the pro-inflammatory milieu synovial fibroblasts (SFs), the main effector cells in disease pathogenesis become activated and hyperplastic while releasing a number of signals that include pro-inflammatory factors and tissue remodeling enzymes. Activated RA SFs in mouse or human arthritic joints express significant quantities of autotaxin (ATX), a lysophospholipase D responsible for the majority of lysophosphatidic acid (LPA) production in the serum and inflamed sites. Conditional genetic ablation of ATX from SFs resulted in attenuation of disease symptoms in animal models, an effect attributed to diminished LPA signaling in the synovium, shown to activate SF effector functions. Here we show that administration of 1-bromo-3(S)-hydroxy-4-(palmitoyloxy)butyl-phosphonate (BrP-LPA), a metabolically stabilized analog of LPA and a dual function inhibitor of ATX and pan-antagonist of LPA receptors, attenuates collagen induced arthritis (CIA) development, thus validating the ATX/LPA axis as a novel therapeutic target in RA. |
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