Invasiveness of synovial fibroblasts is regulated by p53 in the SCID mousein vivo model of cartilage invasion

Objective. In vitro data suggest that the tumor suppressor p53 is criticall y involved in the regulation of proliferation and apoptosis in fibroblast-l ike synoviocytes (FLS). Based on evidence that abnormalities in p53 express ion and function are found in rheumatoid arthritis (RA), we analyzed whethe r inhibition of p53 using gene transfer with the human papilloma virus type 18 (HPV-18) E6 protein results in an increased cellularity and invasivenes s of synovial fibroblasts in vivo. Methods. RA and normal FLS were transduced with a pLXSN-based construct enc oding for the HPV-18 E6 protein or with the pLXSN vector alone. After selec tion with G418, FLS were coimplanted with normal human cartilage under the renal capsule of SCID mice. Parental, nontransduced cells were used as addi tional controls. After 60 days, the implants were removed, and FLS invasion into the cartilage, perichondrocytic degradation, and cellularity were ass essed. 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 <plus/minus> 0.1 and 1.4 +/- 0.3, respectively), but transduction with E6 resulted in clear invasive ness (mean score 2.4 +/- 0.4) as well as increased cellularity. Conclusion. The data suggest that inhibition of endogenous p53 leads to inc reased 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 con tribute to synovial hyperplasia and invasion in RA.