title: Choline kinase inhibition in rheumatoid arthritis.
abstract: OBJECTIVE
  Little is known about targeting the metabolome in non-cancer conditions. Choline kinase (ChoKα), an essential enzyme for phosphatidylcholine biosynthesis, is required for cell proliferation and has been implicated in cancer invasiveness. Aggressive behaviour of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) led us to evaluate whether this metabolic pathway could play a role in RA FLS function and joint damage.
  
  
  METHODS
  Choline metabolic profile of FLS cells was determined by (1)H magnetic resonance spectroscopy ((1)HMRS) under conditions of ChoKα inhibition. FLS function was evaluated using the ChoKα inhibitor MN58b (IC₅₀=4.2 μM). For arthritis experiments, mice were injected with K/BxN sera. MN58b (3 mg/kg) was injected daily intraperitoneal beginning on day 0 or day 4 after serum administration.
  
  
  RESULTS
  The enzyme is expressed in synovial tissue and in cultured RA FLS. Tumour necrosis factor (TNF) and platelet-derived growth factor (PDGF) stimulation increased ChoKα expression and levels of phosphocholine in FLS measured by Western Blot (WB) and metabolomic studies of choline-containing compounds in cultured RA FLS extracts respectively, suggesting activation of this pathway in RA synovial environment. A ChoKα inhibitor also suppressed the behaviour of cultured FLS, including cell migration and resistance to apoptosis, which might contribute to cartilage destruction in RA. In a passive K/BxN arthritis model, pharmacologic ChoKα inhibition significantly decreased arthritis in pretreatment protocols as well as in established disease.
  
  
  CONCLUSIONS
  These data suggest that ChoKα inhibition could be an effective strategy in inflammatory arthritis. It also suggests that targeting the metabolome can be a new treatment strategy in non-cancer conditions.
authors.affiliation: Division of Rheumatology, Allergy and Immunology, UC San Diego School of Medicine, La Jolla, California, USA.
authors.forename: M
authors.initials: M
authors.lastname: Guma
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, UC San Diego School of Medicine, La Jolla, California, USA Departments of Pharmacology, UC San Diego School of Medicine, La Jolla, California, USA Pathology, UC San Diego School of Medicine, La Jolla, California, USA.
authors.forename: E
authors.initials: E
authors.lastname: Sanchez-Lopez
authors.affiliation: Department of Nutritional Sciences & Dell Pediatric Research Institute, University of Texas at Austin, Austin, Texas, USA.
authors.forename: A
authors.initials: A
authors.lastname: Lodi
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, UC San Diego School of Medicine, La Jolla, California, USA Departments of Pharmacology, UC San Diego School of Medicine, La Jolla, California, USA Pathology, UC San Diego School of Medicine, La Jolla, California, USA.
authors.forename: R
authors.initials: R
authors.lastname: Garcia-Carbonell
authors.affiliation: Department of Nutritional Sciences & Dell Pediatric Research Institute, University of Texas at Austin, Austin, Texas, USA.
authors.forename: S
authors.initials: S
authors.lastname: Tiziani
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, UC San Diego School of Medicine, La Jolla, California, USA Departments of Pharmacology, UC San Diego School of Medicine, La Jolla, California, USA Pathology, UC San Diego School of Medicine, La Jolla, California, USA.
authors.forename: M
authors.initials: M
authors.lastname: Karin
authors.affiliation: Division of Translational Oncology, Health Research Institute and University Hospital "Fundación Jiménez Díaz", Madrid, Spain.
authors.forename: J C
authors.initials: JC
authors.lastname: Lacal
authors.affiliation: Division of Rheumatology, Allergy and Immunology, UC San Diego School of Medicine, La Jolla, California, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Firestein
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D002073:Butanes / Q000494:pharmacology / Q000627:therapeutic use*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002794:Choline / Q000378:metabolism; D002797:Choline Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011726:Pyridinium Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: C507944:1,4-(4-4'-Bis-((4-(dimethylamine)pyridinium-1-yl) methyl)diphenyl)butane dibromide; D002073:Butanes; D004791:Enzyme Inhibitors; D011726:Pyridinium Compounds; D002797:Choline Kinase; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D002794:Choline
keywords: Fibroblasts; Rheumatoid Arthritis; Treatment