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FRI0055 Sp1 Inhibitor Modulates The Autocrine Action of Gliostatin/Thymidine Phosphorylase (GLS/TYMP) in Rheumatoid Fibroblast-like Synoviocytes
  1. N. Tatematsu1,
  2. Y. Waguri-Nagaya2,
  3. Y. Kawaguchi1,
  4. K. Ikuta1,
  5. M. Kobayashi1,
  6. M. Nozaki1,
  7. K. Asai3,
  8. M. Aoyama4,
  9. T. Otsuka1
  1. 1Department of Orthopaedic Surgery
  2. 2Department of Joint Surgery for Rheumatic Diseases
  3. 3Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences
  4. 4Department of Pathobiology, Nagoya City University Graduate School of Pharmaceutical Sciences, Nagoya, Japan

Abstract

Background Gliostatin/thymidine phosphorylase (GLS/TYMP) is known to have angiogenic and arthritogenic activities, and aberrant GLS production has been observed in the synovial membranes of rheumatoid arthritis (RA) patients. GLS induces its own expression in cultured fibroblast-like synoviocytes from RA patients (RA-FLSs). The promoters of GLS gene contain binding sites for the DNA binding protein Sp1. Previously, we have reported that the Sp1 transcription factor is essential for the expression of GLS in RA-FLSs and that the Sp1 inhibitor, mithramycin, inhibits the TNF-α-induced expression of GLS in cultured RA-FLSs.

Objectives In this study we examined the inhibitory effect of the Sp1 inhibitor mithramycin on the autocrine activity of GLS expression induced by GLS in cultured RA-FLSs.

Methods Samples of synovial tissue were obtained from 11 patients with RA who were undergoing total knee or elbow arthroplasty or arthroscopic synovectomy. RA-FLSs were cultured with GLS, with or without mithramycin. The expression levels of GLS were determined using reverse transcription-polymerase chain reactions (RT-PCR) and enzyme immunoassay.

Results We investigated GLS mRNA and protein expressions in RA-FLSs treated with or without mithramycin, followed by incubation with GLS. Measuring GLS mRNA and protein levels showed significant induction by GLS alone compared with the control with no GLS. Pre-incubation with mithramycin significantly suppressed this induction.

Conclusions The Sp1 inhibitor, mithramycin, down-regulated the increased expression of GLS in RA-FLSs treated with GLS. Because GLS plays a pathological role in RA, blocking GLS stimulation using mithramycin may suggest novel approaches to anti-rheumatic therapy.

  1. Asai K, Hirano T, Matsukawa K, Kusada J, Takeuchi M, Otsuka T, Matsui N, Kato T. High concentrations of immunoreactive gliostatin/platelet-derived endothelial cell growth factor in synovial fluid and serum of rheumatoid arthritis. Clin Chim Acta 1993, 218:1–4.

  2. Waguri Y, Otsuka T, Sugimura I, Matsui N, Asai K, Moriyama A, Kato T. Gliostatin/platelet-derived endothelial cell growth factor as a clinical marker of rheumatoid arthritis and its regulation in fibroblast-like synoviocytes. Br J Rheumatol 1997, 36:315–321.

  3. Ikuta K, Waguri-Nagaya Y, Kikuchi K, Yamagami T, Nozaki M, Aoyama M, Asai K, Otsuka T. The Sp1 transcription factor is essential for the expression of gliostatin/thymidine phosphorylase in rheumatoid fibroblast-like synoviocytes. Arthritis Res Ther 2012, 14:R87.

Acknowledgement This work was supported by the Japan Society for the Promotion of Science [Grant-in-Aid for Scientific Research (C) 26462309].

Disclosure of Interest None declared

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