2001 Fiscal Year Final Research Report Summary
A new approach for the development of the inhibitor on bone resorption: New drug development from the contact point between ligand and receptor.
| Project/Area Number |
12671802
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Functional basic dentistry
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
AOKI Kazuhiro Graduate school Pharmacology, Tokyo Medical and Dental University, Assistant, 大学院・医歯学総合研究科, 助手 (40272603)
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| Project Period (FY) |
2000 – 2001
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| Keywords | structural biology / TNF / RANK ligand / the inhibition of osteoclastogenesis / cyclic peptide / the inhibition of bone resorption / the contact site between ligand and receptor / drug development / 創薬 |
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| Research Abstract |
The differentiation of osteoclasts, which play a role on bone resorption, requires the interaction of RANK (receptor activator of NF-κB) and RANK ligand. Since these molecules conserve members of the TNF receptor and TNF families, respectively, we tested the ability of a peptide mimic (WP9QY) of a critical contact site on the TNF receptor to inhibit RANK ligand-induced osteoclast formation and activation. The WP9QY peptide dose-dependently inhibited osteoclastogenesis in both the murine co-culture system and in RANK ligand-treated bone marrow cells, as well as RANK ligand-induced bone resorption by isolated osteoclasts. As the inhibitory effect on osteoclastogenesis even using the bone marrow cells from the TNF receptor deficient mice was appeared, it was suggested to be independent of TNF/TNF receptor interactions. Furthermore, WP9QY also prevented the increased in vivo osteoclastogenesis and bone loss induced in mice by a low calcium feeding and by the ovariectomy. These results suggest that the contact site between TNFα and the first loop of domain 3 of the TNF receptor (I) is at least partially conserved in the RANK/RANK ligand interaction and is functionally important for the induction of signaling from RANK in osteoclasts and their precursors. This strategy using a molecular modeling from the crystal structure of the ligand/receptor contact site could lead us a new age for drug development of the inhibitor on bone resorption.
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