Studies of limitin for prevention of bone resorption in bacterial periodontitis

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Periodontitis is a bacterial disease and causes tooth loss due to alveolar bone resorption. Immunological reaction due to periodontitis, that is necessary for prevention of systemic infection of the bacteria, results in excessive osteoclastogenesis. Therefore, it is important for treatment of periodontitis to inhibit osteoclastogenesis without diminishing immunological reactions. Limitin is a type-I interferon (IFN) like cytokine and known to stimulate immune responses. Since the other type-I IFN, IFN-beta, inhibits osteoclastogenesis, I hypothesized that limitin also could prevent osteoclastogenesis with stimulatory effects on immune systems. In this project, I studied the effects of limitin on osteoclastogenesis and the mechanism of the effects. I found that limitin strongly inhibits osteoclastogenesis in vitro cultures. On the other hand, limitin stimulated productions of inflammatory cytokines, such as TNF-alpha and RANKL, by CD3-activated T cells. When explored the mechanism of the inhibitory effect of limitin on osteoclastogenesis, I found that limitin decreases c-fos content in osteoclast precursors and stimulates PKR mRNA expression, which is known to be up-regulated in virul infection and to inhibit protein synthesis. Limitin also inhibited transcription of NFATc1 that is a master gene of osteoclastogenesis and is activated by a combination of transcription factors including c-fos. When PKR mRNA was decreased by siRNA technique, limitin did not diminished c-fos content and osteoclastogenesis. These data suggest that limitin inhibits osteoclastogenesis via PKR-dependent inhibition of c-fos synthesis. Limitin is a potential therapeutic factor for prevention of bone loss in periodontal diseases.