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FRI0340 Inhibition of Collagen-Induced Arthritis in Rats by Intra-Articular Injection with an Inhibitor of the Tyrosine Kinase Epidermal Growth Factor Receptor
  1. C.-R. Wang1,
  2. S.-Y. Chen2,
  3. A.-L. Shiau3,
  4. Y.-T. Li2,
  5. C.-T. Weng1,
  6. I.-M. Jou4,
  7. M.-F. Liu1,
  8. C.-L. Wu2
  1. 1Sect. Rheumatology and Immunology, Dept. Internal Medicine
  2. 2Dept. Biochemistry and Molecular Biology
  3. 3Dept. Microbiology and Immunology
  4. 4Dept. Orthopedics, National Cheng Kung University Medical College, Tainan, Taiwan, Republic of China, -

Abstract

Background Epidermal growth factor receptors (EGFR) can trigger intracellular signal cascades such as PI3K-Akt pathway, and participate in the regulation of cell proliferation. Synovium of rheumatoid arthritis (RA) has high expressions of EGF and EGFR. Therapeutic effects of systemically targeting EGFR have been demonstrated in experimental models, and tyrosine kinase inhibitors (TKI) of EGFR are potential therapeutics in RA. Intra-articular (i.a.) injection, a method bypassing inherited adverse effects associated with the systemic administration, can offer better bioavailability with fewer extra-articular side effects in rheumatoid joint. Indeed, an i.a. injection of biologics such as etanercept can achieve a long-term efficacy in RA monoarthritis without significant adverse events.

Objectives This study explored the possibility of i.a. administration of a small-molecule EGFR TKI (AstraZeneca Pharmaceutics) as a therapeutic strategy in rheumatoid joint by examining its effect on collagen-induced arthritis (CIA) in rats.

Methods The 8 w/o male Sprague-Dawley rats were immunized by intradermal injection of bovine type II collagen with complete Freund's adjuvant. Their ankle joints received an injection of the compound with different concentration after the onset of arthritis. Articular indexes were evaluated following the induction of arthritis, and histological scores were analyzed upon sacrifice of rats. Synovial fibroblasts (SF) were prepared from CIA and RA, and examined for Akt expression and cell proliferation with the EGF stimulation under various concentration of the compound.

Results Injection of the EGFR TKI into CIA joints significantly reduced articular indexes and histological scores. In vitro results of phospho- to total Akt expression ratios and proliferation responses in SF were reduced in the presence of EGFR TKI.

Conclusions These data demonstrate firstly the therapeutic effect of i.a. injection of an EGFR TKI in inhibition of an experimental model of arthritis in rats through the mechanism of reduced Akt activation in SF.

References

  1. Wang CR, et al. Inhibition of experimental collagen-induced arthritis in rats by adenovirus-mediated human kallistatin gene therapy. Ann Rheum Dis 2004;63:S270.

  2. Hennequin LF, et al. Novel 4-anilinoquinazolines with C-6 carbon-linked side chains: synthesis and structure-activity relationship of a series of potent, orally active, EGF receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett 2006;16:2672-6.

  3. Evans CH, et al. Progress in intra-articular therapy. Nat Rev Rheumatol 2014;10:11-22.

Disclosure of Interest None declared

DOI 10.1136/annrheumdis-2014-eular.1358

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