Invasiveness of synovial fibroblasts is regulated by p53 in the SCID mouse in vivo model of cartilage invasion.
OBJECTIVE
In vitro data suggest that the tumor suppressor p53 is critically involved in the regulation of proliferation and apoptosis in fibroblast-like synoviocytes (FLS). Based on evidence that abnormalities in p53 expression and function are found in rheumatoid arthritis (RA), we analyzed whether inhibition of p53 using gene transfer with the human papilloma virus type 18 (HPV-18) E6 protein results in an increased cellularity and invasiveness of synovial fibroblasts in vivo.


METHODS
RA and normal FLS were transduced with a pLXSN-based construct encoding for the HPV-18 E6 protein or with the pLXSN vector alone. After selection with G418, FLS were coimplanted with normal human cartilage under the renal capsule of SCID mice. Parental, nontransduced cells were used as additional controls. After 60 days, the implants were removed, and FLS invasion into the cartilage, perichondrocytic degradation, and cellularity were assessed.


RESULTS
Nontransduced and mock-transduced RA FLS exhibited characteristic invasion into the cartilage (mean +/- SEM scores 2.2 +/- 0.3 and 2.4 +/- 0.2, respectively). Invasion was increased significantly in the E6-transduced RA FLS (mean score 3.1 +/- 0.3; P < 0.05). Inhibition of p53 also resulted in an increase in cellularity. Parental and mock-transduced normal FLS did not exhibit significant invasion (mean score 1.5 +/- 0.1 and 1.4 +/- 0.3, respectively), but transduction with E6 resulted in clear invasiveness (mean score 2.4 +/- 0.4) as well as increased cellularity.


CONCLUSIONS
The data suggest that inhibition of endogenous p53 leads to increased invasiveness and cellularity of RA FLS and may also transform normal FLS to cells that display an aggressive, RA FLS-like behavior. Therefore, abnormalities such as somatic mutations in the p53 tumor suppressor may contribute to synovial hyperplasia and invasion in RA.
University Hospital, Zurich, Switzerland.
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Pap
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Aupperle
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Gay
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Firestein
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Gay
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019902:Chondrocytes / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D016158:Genes, p53 / Q000235:genetics*; D051379:Mice; D016513:Mice, SCID; D023421:Models, Animal; D013583:Synovial Membrane / Q000166:cytology*