ViewpointRheumatoid arthritis and p53: how oxidative stress might alter the course of inflammatory diseases
Section snippets
Oxidative stress in chronic inflammatory disease
Several factors are involved in the development of oxidative stress in the joints of RA patients, including increased pressure in the synovial cavity8, reduced capillary density, vascular changes and an increased metabolic rate of synovial tissue. The generation of ROS could be facilitated by a repetitive ischemia reperfusion injury in the joint8. In addition, locally activated leukocytes can produce ROS. Tissue injury releases iron and copper ions, as well as heme proteins, which are catalytic
Genotoxic effects of oxidative stress
There are extensive data showing that ROS and RNS have the capacity to cause DNA damage and to induce mutations in bacteria and in mammalian cells in vitro15. The generation of oxidizing and nitrating agents also leads to DNA damage in vivo. For example, infection of Syrian golden hamsters with Opisthorchis viverrini increases iNOS activity, causing DNA damage and somatic mutations6. Similarly, inhalation of carbon into rat lungs causes inflammation and epithelial hyperplasia with subsequent
DNA damage in inflammatory disease: accumulation of p53
DNA damage caused by exposure to ionizing radiation, ultraviolet light or some exogenous chemical mutagens that result in DNA strand breakage can induce p53 protein accumulation7. p53 plays a similar role in the response to DNA damage caused by RNS (Ref. 18). For example, exposure of human fibroblasts to NO generated from an NO donor or from overexpression of iNOS might result in accumulation of wild-type p53 (Ref. 18). In addition to the induction of cell growth arrest or apoptosis, wild-type
p53 mutations in inflammatory disease
Genotoxic events usually result in either DNA repair or, if the damage is beyond repair, apoptosis. However, after a non-repairable genotoxic event apoptosis might be inhibited; for example, by overexpression of BCL2 or by mutations of the genes encoding p53 or K-RAS. This permits survival of mutated cells and might lead to further transformation of the cells through a multistep process22. The loss of p53-mediated regulation of iNOS as a result of functional inactivation of p53 could also lead
p53 mutations in rheumatoid arthritis
It has been hypothesized that chronic inflammation in RA might also induce DNA damage severe enough to cause p53 mutations as well as other mutations in cell-cycle and tumor suppressor genes. Indeed, the amount of DNA fragmentation is significantly greater in synovial tissue from RA patients compared with controls29. Furthermore, p53 mutations might explain, in part, the high p53 expression20, 21, the transformed phenotype of FLS (Ref. 1) and the inadequate apoptosis noted in rheumatoid
Closing remarks
DNA damage secondary to chronic inflammation might result in mutations in the p53 gene. Although p53 mutations are not carcinogenic in themselves, they are likely to promote neoplastic transformation in combination with other factors. For example, increased rates of mitosis make it more likely that somatic DNA mutations will avoid the surveillance of DNA repair enzymes. Conceivably, this provides one explanation for the increased risk of cancer in inflammatory conditions characterized by p53
Uncited references (cited in boxes only)
43, 44, 45, 46, 47, 48
Acknowledgements
P.P.T. is supported by a NATO-Science Fellowship and the Dutch Arthritis Foundation (Nationaal Reumafonds); G.S.F., N.J.Z. and D.R.G. receive funding from the NIH.
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