The effect of apoptosis signal-regulating kinase 1 gene transfer on rat collagen induced arthritis

OBJECTIVE: To examine the apoptosis-inducing effect of apoptosis signal-regulating kinase 1 (ASK1) gene transfer into synovial cells in vitro and in vivo. METHODS: An adenovirus vector was constructed so that a constitutively active form of ASK1 gene (ASK1DeltaN) was expressed in the presence of the Cre recombinase. The ASK1DeltaN and Cre adenovirus vectors were cotransduced into cultured synoviocytes derived from patients with rheumatoid arthritis (RA), and apoptosis was evaluated by TUNEL and Hoechst staining. Collagen induced arthritis (CIA) was induced in 8-week-old male DA rats, and 10 days later the 2 adenovirus vectors were coadministered into the ankle joints of the animals. As indicators of severity of arthritis, swelling of the ankle and articular index (AI) scores were evaluated, while histopathological observation of articular tissue was also performed. RESULTS: In the cultured human RA synoviocytes, overexpression of the ASK1DeltaN significantly reduced cell viability and induced apoptosis. In the CIA rats transduced with the ASK1DeltaN gene, arthritis was significantly promoted in terms of the swelling of the ankle joints and elevation of the AI scores. Histopathological observation also revealed that the constitutively active ASK1 induced massive infiltration of inflammatory cells into the synovial membrane as well as proliferation of synovial fibroblasts. Degeneration of the synovial membrane was not evident. CONCLUSION: Adenoviral transduction of ASK1DeltaN induced apoptosis in RA synoviocytes in vitro, but not in CIA synovium in vivo.