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p53 in rheumatoid arthritis synovial fibroblasts at sites of invasion
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  1. C A Seemayer2,
  2. S Kuchen1,
  3. M Neidhart1,
  4. P Kuenzler1,
  5. V Řihošková1,
  6. E Neumann3,
  7. M Pruschy4,
  8. W K Aicher5,
  9. U Müller-Ladner3,
  10. R E Gay1,
  11. B A Michel1,
  12. G S Firestein6,
  13. S Gay1
  1. 1Centre of Experimental Rheumatology and WHO Collaborating Centre for Molecular Biology and Novel Therapeutic Strategies for Rheumatic Diseases, Department of Rheumatology, University Hospital Zürich, Switzerland
  2. 2Institute of Pathology, University Hospital, Basel, Switzerland and Centre of Experimental Rheumatology and WHO Collaborating Centre for Molecular Biology and Novel Therapeutic Strategies for Rheumatic Diseases, Department of Rheumatology, University Hospital Zürich, Switzerland
  3. 3Department of Internal Medicine I, University of Regensburg, D-93042 Regensburg, Germany
  4. 4Radiooncology, Department of Oncology, University Hospital Zürich, CH-8091 Zürich, Switzerland
  5. 5Clinical Research Unit for Rheumatology, Tübingen, Germany
  6. 6Division of Rheumatology, Allergy and Immunology, UCSD School of Medicine, La Jolla, CA 92093, USA
  1. Correspondence to:
    Dr S Gay
    Centre of Experimental Rheumatology, Gloriastrasse 25, CH-8091 Zürich, Switzerland; steffen.gayusz.ch

Abstract

Objective: To analyse the functional response of p53 in rheumatoid arthritis synovial fibroblasts (RASF) in vitro and in vivo and to investigate whether activation of p53 modulates the destructive process of RASF.

Methods: RASF and controls grown on chamber slides were either directly examined with DO7 anti-p53 antibodies by immunofluorescence or irradiated with 10 Gy x rays and analysed time dependently for the expression of p53. The percentage of positive cells was evaluated by a quantitative scoring system. RASF and normal (N) SF cultured in vitro were co-implanted with human cartilage in SCID mice for 60 days. Consecutively, the invasion score was evaluated, and the number of p53 positive cells was determined at the sites of invasion by immunohistochemistry. In addition, synovial tissues from RA, osteoarthritis, and normal synovia were stained with DO7 antibodies.

Results: In vitro the rate of expression of p53 in RASF was low (<5%), but transiently inducible by ionising irradiation (50%). In vitro low p53 expressing RASF disclosed, when invading articular cartilage, a nuclear p53 signal in 20% of the cells, indicating the induction of p53 in a distinct population of RASF during the invasive process.

Conclusions: These data suggest an inductive p53 response at sites of cartilage invasion during the destructive process driven by activated RASF.

  • rheumatoid arthritis
  • p53
  • synovial fibroblasts
  • invasion
  • FSFB, foreskin fibroblasts
  • NSF, normal synovial fibroblasts
  • OA, osteoarthritis
  • PBS, phosphate buffered saline
  • RASF, rheumatoid arthritis synovial fibroblasts
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