title: Autotaxin expression from synovial fibroblasts is essential for the pathogenesis of modeled arthritis.
abstract: Rheumatoid arthritis is a destructive arthropathy characterized by chronic synovial inflammation that imposes a substantial socioeconomic burden. Under the influence of the proinflammatory milieu, synovial fibroblasts (SFs), the main effector cells in disease pathogenesis, become activated and hyperplastic, releasing proinflammatory factors and tissue-remodeling enzymes. This study shows that activated arthritic SFs from human patients and animal models express significant quantities of autotaxin (ATX; ENPP2), a lysophospholipase D that catalyzes the conversion of lysophosphatidylcholine to lysophosphatidic acid (LPA). ATX expression from SFs was induced by TNF, and LPA induced SF activation and effector functions in synergy with TNF. Conditional genetic ablation of ATX in mesenchymal cells, including SFs, resulted in disease attenuation in animal models of arthritis, establishing the ATX/LPA axis as a novel player in chronic inflammation and the pathogenesis of arthritis and a promising therapeutic target.
authors.affiliation: Institute of Immunology, Alexander Fleming Biomedical Sciences Research Center, 16672 Athens, Greece.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Nikitopoulou
authors.forename: Nikos
authors.initials: N
authors.lastname: Oikonomou
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Karouzakis
authors.forename: Ioanna
authors.initials: I
authors.lastname: Sevastou
authors.forename: Nefeli
authors.initials: N
authors.lastname: Nikolaidou-Katsaridou
authors.forename: Zhenwen
authors.initials: Z
authors.lastname: Zhao
authors.forename: Vassilis
authors.initials: V
authors.lastname: Mersinias
authors.forename: Maria
authors.initials: M
authors.lastname: Armaka
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Masayuki
authors.initials: M
authors.lastname: Masu
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Steffen
authors.initials: S
authors.lastname: Gay
authors.forename: George
authors.initials: G
authors.lastname: Kollias
authors.forename: Vassilis
authors.initials: V
authors.lastname: Aidinis
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000503:physiopathology*; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000503:physiopathology*; D002853:Chromatography, Liquid; D005347:Fibroblasts / Q000378:metabolism*; D005697:Galactosides; D017353:Gene Deletion; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles; D008246:Lysophospholipids / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D013583:Synovial Membrane / Q000166:cytology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099189:Lysophospholipase D
chemical_list: D005697:Galactosides; D007211:Indoles; D008246:Lysophospholipids; D010727:Phosphoric Diester Hydrolases; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000099189:Lysophospholipase D; C007293:DAPI; C032881:lysophosphatidic acid; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside