p53 tumor suppressor gene mutations in fibroblast-like synoviocytes from erosion synovium and non-erosion synovium in rheumatoid arthritis

Arthritis Research & Therapy

Gary S Firestein²  Susan Zollman³  Alison Connor³  Edward C Keystone³  Douglas R Green¹  David L Boyle²  Yuji Yamanishi² 

[1]La Jolla Institute of Allergy and Immunology, La Jolla, California, USA

[2]Division of Rheumatology, Allergy, and Immunology, School of Medicine, University of California at San Diego, La Jolla, California, USA

[3]Department of Medicine, University of Toronto, Canada

关键词: rheumatoid arthritis;    p53 mutation;    invasiveness;    fibroblast-like synoviocytes;    erosion;   

Others  :  1101187
DOI  :  10.1186/ar1448

 received in 2004-05-09, accepted in 2004-09-08,  发布年份 2004

【 摘 要 】

Abnormalities in the p53 tumor suppressor gene have been detected in rheumatoid arthritis (RA) and could contribute to the pathogenesis of chronic disease. To determine whether synoviocytes from invasive synovium in RA have an increased number of mutations compared with non-erosion synoviocytes, p53 cDNA subclones from fibroblast-like synoviocytes (FLS) derived from erosion and non-erosion sites of the same synovium were examined in patients requiring total joint replacement. Ten erosion FLS lines and nine non-erosion FLS lines were established from nine patients with RA. Exons 5–10 from 209 p53 subclones were sequenced (114 from erosion FLS, 95 from non-erosion FLS). Sixty percent of RA FLS cell lines and 8.6% of the p53 subclones isolated from FLS contained p53 mutations. No significant differences were observed between the erosion and non-erosion FLS with regard to the frequency or type of p53 mutation. The majority of the mutations were missense transition mutations, which are characteristic of oxidative damage. In addition, paired intact RA synovium and cultured FLS from the same joints were evaluated for p53 mutations. Matched synovium and cultured synoviocytes contained p53 mutations, although there was no overlap in the specific mutations identified in the paired samples. Clusters of p53 mutations in subclones were detected in some FLS, including one in codon 249, which is a well-recognized 'hot spot' associated with cancer. Our data are consistent with the hypothesis that p53 mutations are randomly induced by genotoxic exposure in small numbers of RA synoviocytes localized to erosion and non-erosion regions of RA synovium. The determining factor for invasiveness might be proximity to bone or cartilage rather than the presence of a p53 mutation.

【 授权许可】

   
2004 Yamanishi et al., licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Firestein GS: Evolving concepts of rheumatoid arthritis. Nature 2003, 423:356-361.
• [2]Feldmann M, Maini RN, Bondeson J, Taylor P, Foxwell BM, Brennan FM: Cytokine blockade in rheumatoid arthritis. Adv Exp Med Biol 2001, 490:119-127.
• [3]Joosten LA, Helsen MM, Saxne T, van De Loo FA, Heinegard D, van Den Berg WB: IL-1 alpha beta blockade prevents cartilage and bone destruction in murine type II collagen-induced arthritis, whereas TNF-alpha blockade only ameliorates joint inflammation. J Immunol 1999, 163:5049-5055.
• [4]Muller-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, 149:1607-1615.
• [5]Firestein GS: Invasive fibroblast-like synoviocytes in rheumatoid arthritis. Passive responders or transformed aggressors? Arthritis Rheum 1996, 39:1781-1790.
• [6]Lafyatis R, Remmers EF, Roberts AB, Yocum DE, Sporn MB, Wilder RL: Anchorage-independent growth of synoviocytes from arthritic and normal joints. Stimulation by exogenous platelet-derived growth factor and inhibition by transforming growth factor-beta and retinoids. J Clin Invest 1989, 83:1267-1276.
• [7]Muller-Ladner U, Kriegsmann J, Gay RE, Gay S: Oncogenes in rheumatoid arthritis. Rheum Dis Clin North Am 1995, 21:675-690.
• [8]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, 94:10895-10900.
• [9]Yamanishi Y, Boyle DL, Rosengren S, Green DR, Zvaifler NJ, Firestein GS: Regional analysis of p53 mutations in rheumatoid arthritis synovium. Proc Natl Acad Sci U S A 2002, 99:10025-10030.
• [10]Levine AJ: p53, the cellular gatekeeper for growth and division. Cell 1997, 88:323-331.
• [11]Maacke H, Kessler A, Schmiegel W, Roeder C, Vogel I, Deppert W, Kalthoff H: Overexpression of p53 protein during pancreatitis. Br J Cancer 1997, 75:1501-1504.
• [12]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, 149:2143-2151.
• [13]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, 42:948-953.
• [14]Santhanam U, Ray A, Sehgal PB: Repression of the interleukin 6 gene promoter by p53 and the retinoblastoma susceptibility gene product. Proc Natl Acad Sci U S A 1991, 88:7605-7609.
• [15]Sun Y, Sun Y, Wenger L, Rutter JL, Brinckerhoff CE, Cheung HS: p53 down-regulates human matrix metalloproteinase-1 (collagenase-1) gene expression. J Biol Chem 1999, 274:11535-11540.
• [16]Yamanishi Y, Boyle DL, Pinkoski MJ, Mahboubi A, Lin T, Han Z, Zvaifler NJ, Green DR, Firestein GS: Regulation of joint destruction and inflammation by p53 in collagen-induced arthritis. Am J Pathol 2002, 160:123-130.
• [17]Krishna M, Woda B, Savas L, Baker S, Banner B: Expression of p53 antigen in inflamed and regenerated mucosa in ulcerative colitis and Crohn's disease. Mod Pathol 1995, 8:654-657.
• [18]Ling G, Persson A, Berne B, Uhlen M, Lundeberg J, Ponten F: Persistent p53 mutations in single cells from normal human skin. Am J Pathol 2001, 159:1247-1253.
• [19]Imamura F, Aono H, Hasunuma T, Sumida T, Tateishi H, Maruo S, Nishioka K: Monoclonal expansion of synoviocytes in rheumatoid arthritis. Arthritis Rheum 1998, 41:1979-1986.
• [20]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, 31:315-324.
• [21]Alvaro-Gracia JM, Zvaifler NJ, Firestein GS: Cytokines in chronic inflammatory arthritis. V. Mutual antagonism between interferon-gamma and tumor necrosis factor-alpha on HLA-DR expression, proliferation, collagenase production, and granulocyte macrophage colony-stimulating factor production by rheumatoid arthritis synoviocytes. J Clin Invest 1990, 86:1790-1798.
• [22]Rosengren S, Firestein GS, Boyle DL: Measurement of inflammatory biomarkers in synovial tissue extracts by enzyme-linked immunosorbent assay. Clin Diagn Lab Immunol 2003, 10:1002-1010.
• [23]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 2000, 39:262-266.
• [24]Wink DA, Kasprzak KS, Maragos CM, Elespuru RK, Misra M, Dunams TM, Cebula TA, Koch WH, Andrews AW, Allen JS, et al.: DNA deaminating ability and genotoxicity of nitric oxide and its progenitors. Science 1991, 254:1001-1003.
• [25]Nguyen T, Brunson D, Crespi CL, Penman BW, Wishnok JS, Tannenbaum SR: DNA damage and mutation in human cells exposed to nitric oxide in vitro. Proc Natl Acad Sci U S A 1992, 89:3030-3034.
• [26]Bressac B, Kew M, Wands J, Ozturk M: Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 1991, 350:429-431.
• [27]Puisieux A, Lim S, Groopman J, Ozturk M: Selective targeting of p53 gene mutational hotspots in human cancers by etiologically defined carcinogens. Cancer Res 1991, 51:6185-6189.
• [28]Carbone D, Chiba I, Mitsudomi T: Polymorphism at codon 213 within the p53 gene. Oncogene 1991, 6:1691-1692.
• [29]Reme 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, 111:353-358.
• [30]Kullmann F, Judex M, Neudecker I, Lechner S, Justen HP, Green DR, Wessinghage D, Firestein GS, Gay S, Scholmerich J, Muller-Ladner U: Analysis of the p53 tumor suppressor gene in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 1999, 42:1594-1600.
• [31]Kitasato H, Okamoto R, Kawai S: Absence of p53 mutation in Japanese patients with rheumatoid arthritis: comment on the article by Han et al. Arthritis Rheum 2000, 43:469-470.
• [32]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, 21:78-82.
• [33]Lee SH, Chang DK, Goel A, Boland CR, Bugbee W, Boyle DL, Firestein GS: Microsatellite instability and suppressed DNA repair enzyme expression in rheumatoid arthritis. J Immunol 2003, 170:2214-2220.
• [34]Seemayer CA, Kuchen S, Neidhart M, Kuenzler P, Rihoskova V, Neumann E, Pruschy M, Aicher WK, Muller LU, Gay RE, et al.: p53 in rheumatoid arthritis synovial fibroblasts at sites of invasion. Ann Rheum Dis 2003, 62:1139-1144.
• [35]Walsh NC, Gravallese EM: Bone loss in inflammatory arthritis: mechanisms and treatment strategies. Curr Opin Rheumatol 2004, 16:419-427.
• [36]Han Z, Boyle DL, Shi Y, Green DR, Firestein GS: Dominant-negative p53 mutations in rheumatoid arthritis. Arthritis Rheum 1999, 42:1088-1092.