Abstract
In this study we examined the effect of ribbon-type (circular-type) NF-κB 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 κB 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-κB 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-κB were both greater than those of phosphorothionated NF-κB 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.
Highlights
Osteoclasts are multinucleate giant cells formed by the fusion of hematopoietic cells of the monocyte/macrophage lineage
The structural stability of decoy ODN was ribbon-type NF-κB decoy oligodeoxynucleotide (RNODN) inhibits RANKL-induced osteoclastogenesis To examine the effects of RNODN on osteoclastogenesis in vitro, bone marrow macrophages were incubated with decoy in the presence of RANKL and macrophage colony-stimulating factor (M-CSF) (Figure 3a–c)
Osteoclastogenesis induced by RANKL was inhibited by incubation with RNODN (p < 0.001 compared with the ribbon-type scrambled decoy oligodeoxynucleotide (RSODN)-treated group)
Summary
Osteoclasts are multinucleate giant cells formed by the fusion of hematopoietic cells of the monocyte/macrophage lineage. They are the major resorptive cells of bone [1,2]. Several studies indicate that selective inhibition of NF-κB in osteoclast precursors prevents osteoclast differentiation and function in vitro and in vivo [11,12]. Mice deficient in both the p50 and p65 subunits of NF-κB develop osteopetrosis because of a defect in osteoclast differentiation [13,14]. The importance of the IκB kinase (IKK) β subunit as a transducer of signals from RANK to NF-κB for inflammation-induced bone loss and osteoclastogenesis in vivo was reported [15]
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