Abstract
Spleen tyrosine kinase (Syk), a key mediator of immunoreceptor signaling in inflammatory cells, is essential for immune complex-mediated signal transduction initiated by activated receptors for immunoglobulin G. In collagen-induced arthritis, R788/R406, a novel and potent small molecule Syk inhibitor suppressed clinical arthritis, bone erosions, pannus formation, and synovitis. Serum anti-collagen type II antibody levels were unaltered, while the half-life of exogenous antibody was extended when co-administered with R406. Expression of the targeted kinase (Syk) in synovial tissue correlated with the joint level of inflammatory cell infiltrates and was virtually undetectable in treated rats. Syk inhibition suppressed synovial cytokines and cartilage oligomeric matrix protein (COMP) in serum, suggesting a sensitive and reliable biomarker for R406 activity. These results highlight the role of activating Fcgamma receptors in inflammatory synovitis and suggest that interruption of the signaling cascade with a novel Syk inhibitor may be a useful addition to immunosuppressive disease-modifying anti-rheumatic drugs currently used in the treatment of human autoimmune diseases such as rheumatoid arthritis.
MeSH terms
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Aminopyridines
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Animals
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Arthritis, Rheumatoid / drug therapy*
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Arthritis, Rheumatoid / immunology
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Arthus Reaction / drug therapy
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Bone Resorption / prevention & control*
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Collagen Type II / immunology
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Disease Models, Animal
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Female
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Immunoglobulin G / blood
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Inflammation / immunology
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Inflammation / prevention & control*
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
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Intracellular Signaling Peptides and Proteins / physiology*
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Morpholines
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Oxazines / administration & dosage
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Oxazines / metabolism
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Oxazines / pharmacology*
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Prodrugs / administration & dosage
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Prodrugs / pharmacology*
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / physiology*
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Pyridines / administration & dosage
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Pyridines / metabolism
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Pyridines / pharmacology*
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Pyrimidines
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Rats
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Rats, Sprague-Dawley
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Receptors, IgG / antagonists & inhibitors
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Signal Transduction / drug effects
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Signal Transduction / immunology
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Syk Kinase
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Synovial Fluid / immunology
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Synovitis / drug therapy
Substances
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Aminopyridines
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Collagen Type II
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Immunoglobulin G
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Intracellular Signaling Peptides and Proteins
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Morpholines
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N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine
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Oxazines
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Prodrugs
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Pyridines
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Pyrimidines
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Receptors, IgG
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Protein-Tyrosine Kinases
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SYK protein, human
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Syk Kinase
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Syk protein, rat
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fostamatinib