The tyrosine kinase inhibitor imatinib mesylate suppresses uric acid crystal-induced acute gouty arthritis in mice

PLoS One. 2017 Oct 5;12(10):e0185704. doi: 10.1371/journal.pone.0185704. eCollection 2017.

Abstract

Gouty arthritis is caused by the deposition of monosodium urate (MSU) crystals in joints. Despite many treatment options for gout, there is a substantial need for alternative treatments for patients unresponsive to current therapies. Tyrosine kinase inhibitors have demonstrated therapeutic benefit in experimental models of antibody-dependent arthritis and in rheumatoid arthritis in humans, but to date, the potential effects of such inhibitors on gouty arthritis has not been evaluated. Here we demonstrate that treatment with the tyrosine kinase inhibitor imatinib mesylate (imatinib) can suppress inflammation induced by injection of MSU crystals into subcutaneous air pouches or into the ankle joint of wild type mice. Moreover, imatinib treatment also largely abolished the lower levels of inflammation which developed in IL-1R1-/- or KitW-sh/W-sh mice, indicating that this drug can inhibit IL-1-independent pathways, as well as mast cell-independent pathways, contributing to pathology in this model. Imatinib treatment not only prevented ankle swelling and synovial inflammation when administered before MSU crystals but also diminished these features when administrated after the injection of MSU crystals, a therapeutic protocol more closely mimicking the clinical situation in which treatment occurs after the development of an acute gout flare. Finally, we also assessed the efficiency of local intra-articular injections of imatinib-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles in this model of acute gout. Treatment with low doses of this long-acting imatinib:PLGA formulation was able to reduce ankle swelling in a therapeutic protocol. Altogether, these results raise the possibility that tyrosine kinase inhibitors might have utility in the treatment of acute gout in humans.

MeSH terms

  • Animals
  • Arthritis, Gouty / prevention & control*
  • Crystallization
  • Imatinib Mesylate / administration & dosage
  • Imatinib Mesylate / pharmacology*
  • Injections, Intraperitoneal
  • Mice
  • Mice, Inbred C57BL
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Uric Acid / adverse effects*
  • Uric Acid / chemistry

Substances

  • Protein Kinase Inhibitors
  • Uric Acid
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases

Grant support

L.L.R. acknowledges support from the Arthritis National Research Foundation (ANRF), National Institutes of Health grant K99 AI110645, the European Commission (Marie Skłodowska-Curie Individual Fellowship H2020-MSCA-IF-2014 656086) and the Institut National de la Santé et de la Recherche Médicale (INSERM); P.S. was supported by a Max Kade Fellowship of the Max Kade Foundation and the Austrian Academy of Sciences and a Schroedinger Fellowship of the Austrian Science Fund (FWF): J3399-B21; B.B. was supported by a stipend from the Pasteur - Paris University (PPU) International Ph.D. Program; R.S. was supported by the Lucile Packard Foundation for Children’s Health and the Stanford NIH/NCRR CTSA award number UL1 RR025744; N.G. was the recipient of a fellowship from the French “Fondation pour la Recherche Médicale FRM”; S.R. was supported in part by the George Will Foundation; C.H.C. acknowledges the Chambers Family Foundation Fund for Excellence in Pediatric Research, and the Child Health Research Institute at Stanford for their generous support; S.J.G. acknowledges support from National Institutes of Health grants U19 AI104209, NS 080062, and R01 AR067145 and the Department of Pathology, Stanford University School of Medicine.