Arsenic trioxide induces apoptosis of fibroblast-like synoviocytes and represents antiarthritis effect in experimental model of rheumatoid arthritis.
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.


CONCLUSIONS
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.
Mei
Yifang
Y
Department of Rheumatology, The First Affiliated Hospital, Harbin Medical University, 23 Youzheng St., Nan Gang District, Harbin, China.
Zheng
Yining
Y
Wang
Hui
H
Gao
Juan
J
Liu
Dianxin
D
Zhao
Yanping
Y
Zhang
Zhiyi
Z
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology; D053181:Caspase 8 / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D020287:In Situ Nick-End Labeling; D016328:NF-kappa B / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D051381:Rats; D013583:Synovial Membrane / Q000166:cytology*
D000970:Antineoplastic Agents; D001152:Arsenicals; D016328:NF-kappa B; D010087:Oxides; D053181:Caspase 8; D000077237:Arsenic Trioxide