A metabolically-stabilized phosphonate analog of lysophosphatidic acid attenuates collagen-induced arthritis.
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.
Institute of Immunology, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece.
Ioanna
I
Nikitopoulou
Eleanna
E
Kaffe
Ioanna
I
Sevastou
Ivi
I
Sirioti
Martina
M
Samiotaki
Damian
D
Madan
Glenn D
GD
Prestwich
Vassilis
V
Aidinis
D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D003094:Collagen / Q000009:adverse effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006868:Hydrolysis / Q000187:drug effects; D008244:Lysophosphatidylcholines / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D013379:Substrate Specificity; D000099189:Lysophospholipase D
D003094:Collagen; D008244:Lysophosphatidylcholines; D008246:Lysophospholipids; D010727:Phosphoric Diester Hydrolases; D000099189:Lysophospholipase D; C549092:Brp-LPA