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Logo of annrheumdAnnals of the Rheumatic DiseasesCurrent TOCInstructions for authors
Ann Rheum Dis. Dec 2003; 62(12): 1139–1144.
PMCID: PMC1754413

p53 in rheumatoid arthritis synovial fibroblasts at sites of invasion

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.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Gay S, Gay RE, Koopman WJ. Molecular and cellular mechanisms of joint destruction in rheumatoid arthritis: two cellular mechanisms explain joint destruction? Ann Rheum Dis. 1993 Mar;52 (Suppl 1):S39–S47. [PMC free article] [PubMed]
  • Müller-Ladner U, Gay RE, Gay S. Activation of synoviocytes. Curr Opin Rheumatol. 2000 May;12(3):186–194. [PubMed]
  • Müller-Ladner U, Kriegsmann J, Franklin BN, Matsumoto S, Geiler T, Gay RE, Gay S. Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am J Pathol. 1996 Nov;149(5):1607–1615. [PMC free article] [PubMed]
  • Firestein GS, Nguyen K, Aupperle KR, Yeo M, Boyle DL, Zvaifler NJ. Apoptosis in rheumatoid arthritis: p53 overexpression in rheumatoid arthritis synovium. Am J Pathol. 1996 Dec;149(6):2143–2151. [PMC free article] [PubMed]
  • Lee CS, Portek I, Edmonds J, Kirkham B. Synovial membrane p53 protein immunoreactivity in rheumatoid arthritis patients. Ann Rheum Dis. 2000 Feb;59(2):143–145. [PMC free article] [PubMed]
  • Sugiyama M, Tsukazaki T, Yonekura A, Matsuzaki S, Yamashita S, Iwasaki K. Localisation of apoptosis and expression of apoptosis related proteins in the synovium of patients with rheumatoid arthritis. Ann Rheum Dis. 1996 Jul;55(7):442–449. [PMC free article] [PubMed]
  • Tak PP, Smeets TJ, Boyle DL, Kraan MC, Shi Y, Zhuang S, Zvaifler NJ, Breedveld FC, Firestein GS. p53 overexpression in synovial tissue from patients with early and longstanding rheumatoid arthritis compared with patients with reactive arthritis and osteoarthritis. Arthritis Rheum. 1999 May;42(5):948–953. [PubMed]
  • Firestein GS, Echeverri F, Yeo M, Zvaifler NJ, Green DR. Somatic mutations in the p53 tumor suppressor gene in rheumatoid arthritis synovium. Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10895–10900. [PMC free article] [PubMed]
  • Rème T, Travaglio A, Gueydon E, Adla L, Jorgensen C, Sany J. Mutations of the p53 tumour suppressor gene in erosive rheumatoid synovial tissue. Clin Exp Immunol. 1998 Feb;111(2):353–358. [PMC free article] [PubMed]
  • Inazuka M, Tahira T, Horiuchi T, Harashima S, Sawabe T, Kondo M, Miyahara H, Hayashi K. Analysis of p53 tumour suppressor gene somatic mutations in rheumatoid arthritis synovium. Rheumatology (Oxford) 2000 Mar;39(3):262–266. [PubMed]
  • Kullmann F, Judex M, Neudecker I, Lechner S, Jüsten HP, Green DR, Wessinghage D, Firestein GS, Gay S, Schölmerich J, et al. Analysis of the p53 tumor suppressor gene in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 1999 Aug;42(8):1594–1600. [PubMed]
  • Pap T, Aupperle KR, Gay S, Firestein GS, Gay RE. Invasiveness of synovial fibroblasts is regulated by p53 in the SCID mouse in vivo model of cartilage invasion. Arthritis Rheum. 2001 Mar;44(3):676–681. [PubMed]
  • Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. [PubMed]
  • Pap T, van der Laan WH, Aupperle KR, Gay RE, Verheijen JH, Firestein GS, Gay S, Neidhart M. Modulation of fibroblast-mediated cartilage degradation by articular chondrocytes in rheumatoid arthritis. Arthritis Rheum. 2000 Nov;43(11):2531–2536. [PubMed]
  • Parak WJ, Dannöhl S, George M, Schuler MK, Schaumburger J, Gaub HE, Müller O, Aicher WK. Metabolic activation stimulates acid production in synovial fibroblasts. J Rheumatol. 2000 Oct;27(10):2312–2322. [PubMed]
  • Migita K, Tanaka F, Yamasaki S, Shibatomi K, Ida H, Kawakami A, Aoyagi T, Kawabe Y, Eguchi K. Regulation of rheumatoid synoviocyte proliferation by endogenous p53 induction. Clin Exp Immunol. 2001 Nov;126(2):334–338. [PMC free article] [PubMed]
  • Tak PP, Klapwijk MS, Broersen SF, van de Geest DA, Overbeek M, Firestein GS. Apoptosis and p53 expression in rat adjuvant arthritis. Arthritis Res. 2000;2(3):229–235. [PMC free article] [PubMed]
  • Yamanishi Yuji, Boyle David L, Pinkoski Michael J, Mahboubi Artin, Lin Tesu, Han Zuoning, Zvaifler Nathan J, Green Douglas R, Firestein Gary S. Regulation of joint destruction and inflammation by p53 in collagen-induced arthritis. Am J Pathol. 2002 Jan;160(1):123–130. [PMC free article] [PubMed]
  • Tak PP, Zvaifler NJ, Green DR, Firestein GS. Rheumatoid arthritis and p53: how oxidative stress might alter the course of inflammatory diseases. Immunol Today. 2000 Feb;21(2):78–82. [PubMed]

Figures and Tables

Figure 1
Immunofluorescence for p53 in irradiated and non-irradiated RASF: (A) RASF 6 in passage 3 irradiated with 10 Gy x rays; (B) RASF 6 in passage 3 non-irradiated; (C) RASF 7 in passage 11 irradiated with 10 Gy x rays; (D) RASF 7 in passage 11 non-irradiated. ...
Figure 2
Irradiation of RASF, NSF, and FSFB with 10 Gy x rays and fixation after distinct times. Expression of p53 was determined by immunofluorescence. p53 was transiently induced by ionising irradiation after 2.5 hours in all investigated fibroblast types. ...
Figure 3
Immunohistochemistry of p53 using DO7 antibodies in SCID mice sections of NSF, RASF, and SV40 transformed cells. In NSF, only limited invasion, but hardly any p53 signal was detectable. In RASF, expression of p53 was found in some cartilage invading ...
Figure 4
Quantification of p53 positive cells at sites of invasion in the SCID mouse co-implantation model of RA. Data are expressed as means (SD). On average, p53 was expressed during the invasive process in 20% of cartilage invading RASF. In vitro, the same ...
Figure 5
Immunohistochemistry of p53 with DO7 antibodies of RA tissue specimens and controls. Limited expression of p53 was detected in RA synovium, but no expression in normal synovium. Strong nuclear p53 expression was found in a neurological tumour (positive ...

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