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

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

Reber LL1,2,3,4, Starkl P1,2, Balbino B3,4,5, Sibilano R1,2, Gaudenzio N1,2, Rogalla S6,7, Sensarn S6,7, Kang D6,7,8, Raghu H9,10, Sokolove J9,10, Robinson WH9,10, Contag CH6,7,11, Tsai M1,2, Galli SJ1,2,11.

Author information

1
Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
2
Sean N. Parker Center for Allergy Research, Stanford University School of Medicine, Stanford, California, United States of America.
3
Department of Immunology, Unit of Antibodies in Therapy and Pathology, Institut Pasteur, Paris, France.
4
Institut National de la Santé et de la Recherche Médicale, Paris, France.
5
Université Pierre et Marie Curie, Paris, France.
6
Departments of Bioengineering, Radiology, and Pediatrics Division of Neonatology, Stanford University School of Medicine, Stanford, California, United States of America.
7
Molecular Imaging Program at Stanford, Stanford, California, United States of America.
8
Department of Life Science, Ewha Womans University, Seoul, Korea.
9
Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
10
Geriatric Research Education and Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America.
11
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, United States of America.

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.

PMID:
28982129
PMCID:
PMC5628843
DOI:
10.1371/journal.pone.0185704
[Indexed for MEDLINE]
Free PMC Article

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