2005 Fiscal Year Final Research Report Summary
Contribution of new prostaglandin E_2 synthase to bone resorptive pathology and clinical application of PGES inhibitor
| Project/Area Number |
14370452
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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 | The University of Tokyo |
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Principal Investigator |
YAMAMOTO Motoi The University of Tokyo, Faculty of Medicine, Assistant professor, 医学部附属病院, 助手 (00272584)
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| Co-Investigator(Kenkyū-buntansha) |
KAWAGUCHI Hiroshi The University of Tokyo, Faculty of Medicine, Assistant Professor, 医学部附属病院, 助教授 (40282660)
HOSHI Kazuto The University of Tokyo, Faculty of Medicine, visiting Assistant Professor, 医学部附属病院, 客員助教授 (30344451)
NAKAMURA Kozo The University of Tokyo, Faculty of Medicine, Professor, 医学部附属病院, 教授 (60126133)
MURAKAMI Motoaki The University of Tokyo, Faculty of Medicine, Assistant, 医学部附属病院, 助手 (50396751)
HARA Yukinori The University of Tokyo, Faculty of Medicine, Medical staff, 医学部附属病院, 医員 (30396741)
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| Project Period (FY) |
2002 – 2005
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| Keywords | prostaglandin / bone / bone resorption / knockout mouse / arthritis / osteoporosis / fracture repair / osteoarthritis |
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| Research Abstract |
Among three isozymes of prostaglandin E synthase (PGES), only microsomal PGES-1 (mPGES-1) is the inducible enzyme functionally coupled with cyclooxygenase (COX)-2. First, we confirmed that only mPGES-1 was induced by bone resorptive cytokines in cultured mouse primary osteoblasts and bone marrow cells. An antisense oligonucleotide blocking mPGES-1 expression inhibited not only PGE_2 production, but also osteoclastogenesis and bone resorption stimulated by the cytokines. Next, we analyzed the phenotypes of mPGES-1 knockout (KO) mice. mPGES-1 KO mice developed and grew normally without abnormalities of major organs including bone under physiological conditions. Hence, we investigated the involvement of mPGES-1 in several pathological conditions using mouse experimental models. Pain nociception assessed by the acetic acid writhing response, and inflammatory granulation tissue formation in the dorsum induced by subcutaneous implantation of a cotton thread were significantly reduced in KO mice relative to WT mice. In collagen antibody-induced arthritis model, mPGES-1 KO mice exhibited inhibition not only of inflammation, but also of joint destruction. Bone decreases after ovariectomy and unloading by tail-suspension were similarly seen in KO and WT mice. Fracture healing was inhibited in mPGES-1 KO mice with smaller callus formation as compared with WT mice. Reintroduction of mPGES-1 to the KO fractured site using an adenovirus vector restored the callus formation. In an experimental knee OA model, cartilage destruction was similarly seen in WT and mPGES-1 KO mice. An inhibitor of mPGES-1 is expected to be a highly selective agent against several disorders, and might replace COX-2 inhibitors ; however, it should be cautiously applied to patients with bone fracture.
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