OBJECTIVE: recent studies have demonstrated that rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) proliferate as fiercely as tumor cells. Induction of apoptosis in RA FLS therefore provides a new approach for the inhibition of joint destruction. Arsenic trioxide (As(2)O(3)) was reported to be an effective apoptosis inducer in a variety of cell types. We investigated the possible effect of As(2)O(3) on apoptosis induction of RA FLS and the mechanisms involved in this process. METHODS: apoptosis was determined by flow cytometric analysis, terminal deoxynucleotide transferase-mediated dUTP nick end-labeling, and transmission electron microscopy. The activity and messenger RNA (mRNA) expression of nuclear factor-κB (NF-κB) was then detected by ELISA and real-time polymerase chain reaction, respectively. Activities of caspase-3 and caspase-8 were evaluated using luminogenic substrates. The effect of As(2)O(3) on the morphology of rats with collagen-induced arthritis was evaluated under a light microscope after H&E staining. RESULTS: as(2)O(3) significantly enhanced the apoptosis of RA FLS. It suppressed the DNA-binding activity and mRNA expression level of NF-κB, probably by inhibiting tumor necrosis factor-α-induced activation of NF-κB. As(2)O(3) treatment significantly increased the activity of both caspase-3 and caspase-8. Morphological analysis revealed histological recovery in the synovial membrane. Synovial hyperplasia and inflammation in the joints were effectively inhibited. CONCLUSION: as(2)O(3) represents an apoptotic effect on RA FLS through NF-κB signaling pathway, and this process is mediated by the activation of caspase cascade. Treatment with As(2)O(3) significantly improved the pathologic changes of collagen-induced arthritis and may have potential for treatment of RA.
OBJECTIVE: recent studies have demonstrated that rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) proliferate as fiercely astumor cells. Induction of apoptosis in RA FLS therefore provides a new approach for the inhibition of joint destruction. Arsenic trioxide (As(2)O(3)) was reported to be an effective apoptosis inducer in a variety of cell types. We investigated the possible effect of As(2)O(3) on apoptosis induction of RA FLS and the mechanisms involved in this process. METHODS: apoptosis was determined by flow cytometric analysis, terminal deoxynucleotide transferase-mediated dUTP nick end-labeling, and transmission electron microscopy. The activity and messenger RNA (mRNA) expression of nuclear factor-κB (NF-κB) was then detected by ELISA and real-time polymerase chain reaction, respectively. Activities of caspase-3 and caspase-8 were evaluated using luminogenic substrates. The effect of As(2)O(3) on the morphology of rats with collagen-induced arthritis was evaluated under a light microscope after H&E staining. RESULTS:as(2)O(3) significantly enhanced the apoptosis of RA FLS. It suppressed the DNA-binding activity and mRNA expression level of NF-κB, probably by inhibiting tumor necrosis factor-α-induced activation of NF-κB. As(2)O(3) treatment significantly increased the activity of both caspase-3 and caspase-8. Morphological analysis revealed histological recovery in the synovial membrane. Synovial hyperplasia and inflammation in the joints were effectively inhibited. CONCLUSION:as(2)O(3) represents an apoptotic effect on RA FLS through NF-κB signaling pathway, and this process is mediated by the activation of caspase cascade. Treatment with As(2)O(3) significantly improved the pathologic changes of collagen-induced arthritis and may have potential for treatment of RA.