2006 Fiscal Year Final Research Report Summary
Analysis of regulatory mechanisms of bone metabolism utilizing TAK1-conditional knockout mice
| Project/Area Number |
16390434
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | Saitama Medical University (2006)
Tokyo Medical and Dental University (2004-2005) |
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Principal Investigator |
SATO Kojiro Saitama Medical University, Faculty of Medicine, Assistant professor, 医学部, 講師 (10372434)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAYANAGI Hiroshi Tokyo Medical and Dental University, Graduate School, Professor, 大学院医歯学総合研究科, 教授 (20334229)
ASAGIRI Masataka Tokyo Medical and Dental University, Graduate School, Assistant professor, 大学院医歯学総合研究科, 特任講師 (20372435)
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| Project Period (FY) |
2004 – 2006
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| Keywords | osteoclast / bone metabolism / kinase / transcription factor / immunology / osteoporosis / rheumatoid arthritis / T cell |
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| Research Abstract |
Osteoclasts are specially differentiated multinucleated macrophages that resorb bone matrix. Their function is essential for normal bone metabolism ; their dysfunction causes osteopetrosis and their hyper-function can lead to osteoporosis or bone destruction observed in rheumatoid arthritis. Thus, it is important to understand the mechanisms of their differentiation and functions.
We previously reported that a transcription factor NFATc1 is strongly induced in the course of osteoclastogenesis in vitro. During the period covered by this grant, we showed that (1) NFATc1 is indeed required for osteoclastogenesis in vivo and that (2) one of immunoreceptors, OSCAR, is a target of NFATc1 whilst it is involved in activation of NFATc1, thus constituting a novel positive feedback system. We also discovered a novel T helper cell subset, now called Th17 cells, which can enhance osteoclastogenesis. Th1 and Th2 cells strongly suppressed osteoclastogenesis, casting doubt on the notion that rheumatoid
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arthritis (RA), in which bone destruction is one of the characteristics, is a Th1 disease. IL-17 that is produced by Th17 cells and IL-23 that is required for Th17 cell expansion could be promising targets for the treatment of RA. Finally, we found that calcium/calmodulin-dependent kinases (CaMKs) are involved in osteoclastogenesis. Among them, we showed through knockdown experiments that CaMKIV is especially important. In fact, CaMKIV KO mice showed increased bone mass (osteopetrosis) because of reduced osteoclastogenesis. The molecular target of CaMKIV seems to be a transcription factor CREB, which is required for NFATc1 induction, because forced expression of constitutive active CREB can rescue osteoclast differentiation in the presence of CaMK inhibitor in vitro. In mouse models bone destruction (an LPS injection model) and osteoporosis (an ovariectomy model), the CaMK inhibitor ameriolated both of the diseases. Thus, CaMK-CREB pathway is also a promising target in the treatment of bone diseases. Less
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