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Choline kinase inhibition in rheumatoid arthritis
  1. M Guma1,
  2. E Sanchez-Lopez2,3,4,
  3. A Lodi5,
  4. R Garcia-Carbonell2,3,4,
  5. S Tiziani5,
  6. M Karin2,3,4,
  7. J C Lacal6,
  8. G S Firestein1
  1. 1Division of Rheumatology, Allergy and Immunology, UC San Diego School of Medicine, La Jolla, California, USA
  2. 2Laboratory of Gene Regulation and Signal Transduction, UC San Diego School of Medicine, La Jolla, California, USA
  3. 3Departments of Pharmacology, UC San Diego School of Medicine, La Jolla, California, USA
  4. 4Pathology, UC San Diego School of Medicine, La Jolla, California, USA
  5. 5Department of Nutritional Sciences & Dell Pediatric Research Institute, University of Texas at Austin, Austin, Texas, USA
  6. 6Division of Translational Oncology, Health Research Institute and University Hospital “Fundación Jiménez Díaz”, Madrid, Spain
  1. Correspondance to Dr Monica Guma, Division of Rheumatology, Allergy and Immunology, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0656, USA; mguma{at}ucsd.edu

Abstract

Objectives 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 1H magnetic resonance spectroscopy (1HMRS) 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.

  • Rheumatoid Arthritis
  • Fibroblasts
  • Treatment

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