Studies on the contribution of c-fos/AP-1 to arthritic joint destruction

J Clin Invest. 1997 Mar 15;99(6):1210-6. doi: 10.1172/JCI119277.


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.

MeSH terms

  • Animals
  • Arthritis / etiology*
  • Arthritis / genetics
  • Arthritis / pathology*
  • Collagen
  • Injections, Intraperitoneal
  • Knee Joint
  • Male
  • Mice
  • Mice, Inbred DBA
  • Oligonucleotides / administration & dosage
  • Oligonucleotides / metabolism
  • Proto-Oncogene Proteins c-fos / physiology*
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / physiology*
  • Transfection


  • Oligonucleotides
  • Proto-Oncogene Proteins c-fos
  • Transcription Factor AP-1
  • Collagen