| Budget Amount *help |
¥6,800,000 (Direct Cost: ¥6,800,000)
Fiscal Year 1993: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1992: ¥4,600,000 (Direct Cost: ¥4,600,000)
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| Research Abstract |
We report here that leukocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) are involved in osteoclast development. Osteoclast development was observed on co-culture of mouse spleen cells and mouse bone marrow derived clonal stromal cells, TMS-14, in the presence of 1alpha, 25-dihydroxyvitamin D-3 (1alpha, 25-(OH)_2D_3) for 8 days, and quantified with respect to tartrate-resistant acid phosphatase (TRACP) activity. When either one of the monoclonal antibodies (MAbs) to mouse LFA-1 and mouse ICAM-1 was added to the co-culture system, the TRACP activity was significantly inhibited. The experiment in which one-day treatment with each of these MAbs was performed suring the 8 days of cultivation showed that the inhibitory effects of both MAbs on the TRACP activity at 8 days were observed from an early stage of the culture, but were more notable at a later stage (days 4-6). As the expression of ICAM-1 was observed on both spleen cells and TMS-14, we nex
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t examined whether the interaction between stromal cells and osteoclast progenitors or among osteoclast progenitors was more important for osteoclast development. To determine this, rat spleen cells and a MAb to rat ICAM-1 were used instead of those of mouse. When MAb to rat ICAM-1 or mouse ICAM-1 was added to the co-culture system of rat spleen cells and TMS-14, the inhibitory effect of the MAb to rat ICAM-1 was mainly observed at a later stage of the culture period and that of anti-mouse ICAM-1 antibody was only observed at an earlier stage. These results indicate that adhesion molecules LFA-1 and ICAM-1 may play a role in osteoclast development via interaction between stromal cells and osteoclast progenitors as well as among osteoclast progenitors.
Angiogenesis plays a significant role in various pathological states, including the progressive growth of solid tumors, rheumatoid arthritis, psoriasis, and diabetic retinopathy, in addition to its crucial role in embryonic development. Recent studies have revealed that an angiogenesis inhibitor is efficacious for these so-called angiogenic diseases. In the previous studies, we found that retinoids and vitamin D_3 analogs, which are known to exhibit cell differentiation-modulating activity, effectively inhibit angiogenesis in vivo, thus forming the basis of our working hypothesis that a modulator of cell differentiation is capable of affecting angiogenesis. In this study, to verify this hypothesis further, radicicol(syn.monorden ; 5-chloro-6-(7, 8-epoxy-10-hydroxy-2-oxo-3, 5-undecadienyl)-beta-resorcylic acid mu-lactone), a microbial cell differentiation modulator from a fungus, a strain of Neocosmospora tenuicristata, was examined for its anti-angiogenic activity in a bioassay system involving chorioallantoic membranes of growing chick embryos. The microbial cell differentiation modulator dose dependently inhibited embryonic angiogenesis, the ID_<50> value being 200 ng/egg. Radicicol also inhibited both the proliferation of and plasminogen activator production by vascular endothelial cells in the nM concentration range in a concentration-dependent manner, suggesting the possible involvement of these inhibitory effects in the anti-angiogenic action of the microbial product. These results indicate that radicicol might be a potential drug for treating different angiogenesis-dependent diseases, such as solid tumors, psoriasis, rheumatoid arthritis, and diabetic retinopathy. Less
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