2003 Fiscal Year Final Research Report Summary
Development of treatment for bone destructive diseases by interfering osteoclastgenesis
| Project/Area Number |
14571405
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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 |
Orthopaedic surgery
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| Research Institution | Juntendo University |
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Principal Investigator |
KUROSAWA Hisashi Juntendo University, Professor, 医学部, 教授 (50010301)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAYANAGI Hiroshi Tokyo Medical and Dental University, Professor, 大学院・医歯学総合研究科・顎顔面頸部機能再建学系, 教授 (20334229)
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| Project Period (FY) |
2002 – 2003
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| Keywords | Bone destructive disease / RANKL signal / NFATcl / osteoclastogenesis / AAV vector / Antirheumatic drug |
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| Research Abstract |
Several lines of evidence indicate that bone destruction in arthritis or metastatic bone disease is mainly mediated by bone-resorbing osteoclasts. Therefore, osteoclast is one of the main targets to suppress bone destruction in such pathologic conditions. Bone-marrow derived monocyte/macrophage precursor cells differentiate into osteoclasts under signaling by RANKL. To introduce molecules to regulate osteoclastogenesis, AAV vector was infected into osteoclast precursors and mature osteoclasts. AAV vector efficiently introduced GFP gene only in mature osteoclasts not in precursors. The efficiency of gene delivery of AAV vector was confirmed but was not sufficient to prevent bone destruction. RANKL signaling is essential for terminal differentiation of precursor cells into osteogenesis. We show that RANKIL selectively induces NFATc1 expression. NFATc1-deficient embryonic stem cells fail to differentiate into osteoclasts in response to RANKL stimulation and that ectopic expression of NFATc1 causes precursor cells to undergo efficient differentiation without RANKIL. Thus, it is indicated that NFATc1 may be a master switch to regulate osteoclastogenesis. The antirheumatic drug leflunomide blocked de novo pyrymidine synthesis and RANKL-induced calcium signaling in osteoclast precursor cells in vitro. As a result, the induction of nuclear factor of activated T cells cl(NFATc1) was strongly inhibited. This direct inhibitory action of leflunomide on osteoclast differentiation constitutes an important aspect in the amelioration of bone destruction. Strong and selective expression of NFATc1 was observed in multinucleated osteoclasts at the bone-synovium interface in patients with RA. NFATc1 might be a promising target to ameliorate bone destructive condition.
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