Studies on the contribution of c-fos/AP-1 to arthritic joint destruction.
Features characteristic to rheumatoid joint destruction, including synovial overgrowth and bone resorption, are experimentally produced by augmenting c-fos gene expression. We tested here if arthritic joint destruction was inhibited upon inactivation of the c-fos/AP-1 signal by administering short double-stranded AP-1 DNA oligonucleotides into mice with collagen-induced arthritis to compete for the binding of AP-1 in vivo at the promoter binding site. Arthritic joint destruction was inhibited in a sequence-specific and dose-dependent manner by oligonucleotides containing the AP-1 sequence. The oligonucleotides inhibited gene expression at the transcriptional level. Nucleotide sequences besides AP-1 also appeared to be important structurally for binding of AP-1 onto DNA and for the stability of oligonucleotides against nucleases. Immunohistochemical chase experiment administering biotinylated oligonucleotides into arthritic mice showed that AP-1 oligonucleotides reached the inflamed joint. Thus, activation of c-fos/AP-1 appears essentially important in arthritic joint destruction.
Shiozawa
S
S
Kobe University School of Medicine, Faculty of Health Science, Sumaku, Japan.
Shimizu
K
K
Tanaka
K
K
Hino
K
K
D000818:Animals; D001168:Arthritis / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D003094:Collagen; D007274:Injections, Intraperitoneal; D007719:Knee Joint; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009841:Oligonucleotides / Q000008:administration & dosage / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000502:physiology*; D014162:Transfection
D009841:Oligonucleotides; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D003094:Collagen