p53 tumor suppressor gene mutations in fibroblast-like synoviocytes from erosion synovium and non-erosion synovium in rheumatoid arthritis.
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.
Yamanishi
Yuji
Y
Department of Rheumatology, Hiroshima City Hospital, Hiroshima, Japan.
Boyle
David L
DL
Green
Douglas R
DR
Keystone
Edward C
EC
Connor
Alison
A
Zollman
Susan
S
Firestein
Gary S
GS
D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000473:pathology*; D002460:Cell Line; D002999:Clone Cells / Q000378:metabolism; D003062:Codon / Q000235:genetics; D004252:DNA Mutational Analysis; D005347:Fibroblasts / Q000737:chemistry / Q000473:pathology*; D016158:Genes, p53; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis; D016254:Mutagenesis, Insertional; D020125:Mutation, Missense; D017354:Point Mutation; D017384:Sequence Deletion; D013583:Synovial Membrane / Q000737:chemistry / Q000473:pathology*
D003062:Codon; D020781:Matrix Metalloproteinase 1