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

Yamanishi Y, Boyle DL, Green DR, Keystone EC, Connor A, Zollman S, Firestein GS - Arthritis Res. Ther. (2004)

Bottom Line: 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.The determining factor for invasiveness might be proximity to bone or cartilage rather than the presence of a p53 mutation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Rheumatology, Hiroshima City Hospital, Hiroshima, Japan.

ABSTRACT
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.

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Types of p53 mutations in rheumatoid arthritis fibroblast-like synoviocytes (FLS). Because no differences were observed between erosion FLS and non-erosion FLS (see Table 1), results were pooled.
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Figure 1: Types of p53 mutations in rheumatoid arthritis fibroblast-like synoviocytes (FLS). Because no differences were observed between erosion FLS and non-erosion FLS (see Table 1), results were pooled.

Mentions: As in previous reports [8,9,23], most p53 mutations (eight of nine in erosion FLS and eight of nine in non-erosion FLS) were transition mutations (i.e. G>A or C>T), which are characteristic of mutations caused by oxidative damage [24,25], and no transversion mutations (i.e. G>T, A>T, C>A, C>G) were seen (see Fig. 1 for the pooled data). One single base deletion and one multinucleotide insertion were detected. The majority of p53 mutations (78%) were missense (see Fig. 1 for pooled data). Most of the mutations were identified in a single subclone, although multiple copies of one mutation in codon 321 AAA to GAA were observed in an erosion FLS line. These data suggest that the frequency and types of mutations are similar in FLS isolated from either sites of erosion or from regions that are not invading into bone or cartilage.


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

Yamanishi Y, Boyle DL, Green DR, Keystone EC, Connor A, Zollman S, Firestein GS - Arthritis Res. Ther. (2004)

Types of p53 mutations in rheumatoid arthritis fibroblast-like synoviocytes (FLS). Because no differences were observed between erosion FLS and non-erosion FLS (see Table 1), results were pooled.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1064878&req=5

Figure 1: Types of p53 mutations in rheumatoid arthritis fibroblast-like synoviocytes (FLS). Because no differences were observed between erosion FLS and non-erosion FLS (see Table 1), results were pooled.
Mentions: As in previous reports [8,9,23], most p53 mutations (eight of nine in erosion FLS and eight of nine in non-erosion FLS) were transition mutations (i.e. G>A or C>T), which are characteristic of mutations caused by oxidative damage [24,25], and no transversion mutations (i.e. G>T, A>T, C>A, C>G) were seen (see Fig. 1 for the pooled data). One single base deletion and one multinucleotide insertion were detected. The majority of p53 mutations (78%) were missense (see Fig. 1 for pooled data). Most of the mutations were identified in a single subclone, although multiple copies of one mutation in codon 321 AAA to GAA were observed in an erosion FLS line. These data suggest that the frequency and types of mutations are similar in FLS isolated from either sites of erosion or from regions that are not invading into bone or cartilage.

Bottom Line: 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.The determining factor for invasiveness might be proximity to bone or cartilage rather than the presence of a p53 mutation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Rheumatology, Hiroshima City Hospital, Hiroshima, Japan.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus