Inhibitory effect of ribbon-type NF-kappaB decoy oligodeoxynucleotides on osteoclast induction and activity in vitro and in vivo.
In this study we examined the effect of ribbon-type (circular-type) NF-kappaB decoy oligodeoxynucleotides (RNODN) on osteoclast induction and activity. We extracted bone marrow cells from the femurs of rats and incubated non-adherent cells with receptor activator of nuclear factor kappaB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). First, transfer efficiency into osteoclasts and their precursors, resistance to exonuclease, and binding activity of decoy to NF-kappaB were examined. Next, to examine the effect of RNODN on osteoclast induction and activity, osteoclast differentiation and pit formation assays were performed. RNODN were injected into the ankle joints of rats with collagen-induced arthritis. Joint destruction and osteoclast activity were examined by histological study. The resistance of RNODN to exonuclease and their binding activity on NF-kappaB were both greater than those of phosphorothionated NF-kappaB decoy oligodeoxynucleotides. The absolute number of multinucleate cells scoring positive for tartrate-resistant acid phosphatase was significantly decreased in the RNODN-treated group. The average calcified matrix resorbed area was significantly decreased in the RNODN-treated group. Histological study showed marked suppression of joint destruction and osteoclast activity by intra-articular injection of RNODN. These results suggest the inhibitory effect of RNODN on the induction and activity of osteoclasts. Direct intra-articular injection of RNODN into the joints may be an effective strategy for the treatment of arthritis.
Kunugiza
Yasuo
Y
Division of Clinical Gene Therapy, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Tomita
Tetsuya
T
Tomita
Naruya
N
Morishita
Ryuichi
R
Yoshikawa
Hideki
H
D000818:Animals; D000843:Ankle Joint / Q000187:drug effects / Q000473:pathology; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects; D001862:Bone Resorption / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004355:Drug Stability; D005260:Female; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D007270:Injections, Intra-Articular; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010010:Osteoclasts / Q000166:cytology* / Q000473:pathology; D053245:RANK Ligand / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew
D005456:Fluorescent Dyes; D016328:NF-kappa B; C468119:NF-kappaB decoy; D050778:NFATC Transcription Factors; D009838:Oligodeoxyribonucleotides; D053245:RANK Ligand; D016650:Fluorescein-5-isothiocyanate