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Tyrosine kinases as targets for the treatment of rheumatoid arthritis

Nature Reviews Rheumatology volume 5, pages 317–324 (2009)Cite this article

Abstract

As critical regulators of numerous cell signaling pathways, tyrosine kinases are implicated in the pathogenesis of several diseases, including rheumatoid arthritis (RA). In the absence of disease, synoviocytes produce factors that provide nutrition and lubrication for the surrounding cartilage tissue; few cellular infiltrates are seen in the synovium. In RA, however, macrophages, neutrophils, T cells and B cells infiltrate the synovium and produce cytokines, chemokines and degradative enzymes that promote inflammation and joint destruction. In addition, the synovial lining expands owing to the proliferation of synoviocytes and infiltration of inflammatory cells to form a pannus, which invades the surrounding bone and cartilage. Many of these cell responses are regulated by tyrosine kinases that operate in specific signaling pathways, and inhibition of a number of these kinases might be expected to provide benefit in RA.

Key Points

  • Rheumatoid arthritis (RA) is characterized by leukocyte infiltration, synoviocyte hyperplasia and osteoclastogenesis, and tyrosine kinases have key roles in the signaling pathways that regulate these processes

  • Inhibition of platelet-derived growth factor receptors, vascular endothelial growth factor receptors and TIE receptors might reduce synovial hyperplasia and angiogenesis

  • Inhibition of colony-stimulating factor receptor-1 and Src might reduce monocyte maturation and osteoclastogenesis

  • Blocking signaling through Bruton's tyrosine kinase might reduce B-cell and T-cell activation

  • Blocking KIT activation might induce mast cell apoptosis, thereby reducing the production of inflammatory cytokines and degradative molecules in the synovium

  • Imatinib, which inhibits several tyrosine kinases, and more-specific inhibitors of Janus kinases and Syk, have already shown efficacy in the treatment of RA; however, toxicity remains an issue

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Figure 1: Cellular responses mediated by tyrosine kinases that contribute to the pathogenesis of rheumatoid arthritis.
Figure 2: Activation of tyrosine kinases.

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Acknowledgements

We thank members of the Robinson laboratory for their scientific input. This work was funded by NIH NHLBI contract N01 HV 28183, NIH NIAMS R01 AR-054822, and Veterans Affairs Health Care System funding to W. H. Robinson; Stanford University Program in Immunology training grant support to C. D'Aura Swanson; and an NIH F31 Fellowship Award and a Lieberman Fellowship Award to R. T. Paniagua.

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  1. Division of Immunology and Rheumatology, Stanford, CA, USA

    Tamsin M. Lindstrom & William H. Robinson

  2. Stanford University School of Medicine, Stanford, CA, USA

    Christina D'Aura Swanson & Ricardo T. Paniagua

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Correspondence to William H. Robinson.

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D'Aura Swanson, C., Paniagua, R., Lindstrom, T. et al. Tyrosine kinases as targets for the treatment of rheumatoid arthritis. Nat Rev Rheumatol 5, 317–324 (2009). https://doi.org/10.1038/nrrheum.2009.82

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