Inhibition of
NF-kappaB is known to be effective in reducing both
inflammation and bone destruction in animal models of
arthritis. Our previous study demonstrated that a small cell-permeable
NF-kappaB inhibitor,
dehydroxymethylepoxyquinomicin (DHMEQ), suppresses expression of proinflammatory
cytokines and ameliorates mouse
arthritis. It remained unclear, however, whether DHMEQ directly affects osteoclast precursor cells to suppress their differentiation to mature osteoclasts in vivo. The effect of DHMEQ on human osteoclastogenesis also remained elusive. In the present study, we therefore examined the effect of DHMEQ on osteoclastogenesis using a mouse
collagen-induced arthritis model, and using culture systems of fibroblast-like synovial cells obtained from patients with
rheumatoid arthritis, and of osteoclast precursor cells from peripheral blood of healthy volunteers. DHMEQ significantly suppressed formation of osteoclasts in arthritic joints, and also suppressed expression of NFATc1 along the inner surfaces of bone lacunae and the eroded bone surface, while serum levels of soluble
receptor activator of NF-kappaB ligand (RANKL),
osteoprotegerin and
macrophage colony-stimulating factor were not affected by the treatment. DHMEQ also did not suppress spontaneous expression of RANKL nor of
macrophage colony-stimulating factor in culture of fibroblast-like synovial cells obtained from patients with
rheumatoid arthritis. These results suggest that DHMEQ suppresses osteoclastogenesis in vivo, through downregulation of NFATc1 expression, without significantly affecting expression of upstream molecules of the RANKL/
receptor activator of NF-kappaB/
osteoprotegerin cascade, at least in our experimental condition. Furthermore, in the presence of RANKL and
macrophage colony-stimulating factor, differentiation and activation of human osteoclasts were also suppressed by DHMEQ, suggesting the possibility of future application of
NF-kappaB inhibitors to
rheumatoid arthritis therapy.