2000 Fiscal Year Final Research Report Summary
Study on signal transduction in osteoclastogenesis for the development of anti-osteoporosis drugs.
| Project/Area Number |
11557139
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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 | 展開研究 |
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| Research Field |
Functional basic dentistry
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| Research Institution | Showa University |
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Principal Investigator |
TAKAHASHI Naoyuki School of Dentistry, Showa University Associate Professor, 歯学部, 助教授 (90119222)
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| Co-Investigator(Kenkyū-buntansha) |
KATAGIRI Takenobu School of Dentistry, Showa University Lecturer, 歯学部, 講師 (80245802)
UDAGAWA Nobuyuki School of Dentistry, Showa University Lecturer, 歯学部, 講師 (70245801)
SHINKI Toshimasa School of Dentistry, Showa University Lecturer, 歯学部, 講師 (90138420)
TAKAMI Masamichi School of Dentistry, Showa University Assistant, 歯学部, 助手 (80307058)
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| Project Period (FY) |
1999 – 2000
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| Keywords | Osteoclast / Osteoblast / Inflammatory cytokines / Calcium / BMP / RANKL / OPG / Osteoporosis |
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| Research Abstract |
Inhibition of signal transduction for osteoclastogenesis is thought to provide important information for development of anti-osteoporosis drugs. We have succeeded in molecular cloning of an essential factor for osteoclastogenesis, RANKL, which is expressed as a membrane associated factor in osteoblasts in response to many bone-resorbing factors. Using culture systems for osteoclast formation, we have studied signal transduction for osteoclastogenesis including RANK-RANKL signaling. The findings obtained from the study are as follows. (1) TNFα stimulated osteoclastogenesis in bone marrow-derived macrophage cultures in the presence of M-CSF.(2) SaOS-4/3, a subclone of the human osteosarcoma cell line SaOS-2, established by transfecting the human PTH/PTHrP receptor cDNA, supported osteoclast formation in response to PTH in co-culture with mouse bone marrow cells. Expression of mRNAs for RANKL and M-CSF by SaOS-4/3 cells was up-regulated in response to PTH.Both factors were expressed as membrane-associated factors. (3) Ionomycin and A23187 stimulated osteoclast formation in mouse co-cultures of bone marrow cells and osteoblasts. We also found that PMA, an activator of protein kinase C, stimulated osteoclast formation in the co-culture though up-regulation of RANKL expression in osteoblasts. (4) BMP-2 markedly enhanced osteoclast differentiation induced by RANKL and M-CSF.Addition of a soluble form of BMP receptor type-IA to the culture inhibited not only osteoclast formation induced by RANKL and BMP-2, but also the basal osteoclast formation supported by RANKL alone. Both bone marrow macrophages and mature osteoclasts expressed BMP-2 and BMP receptor type IA mRNAs. These findings provide important information for the development of anti-osteoporosis drugs.
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[Publications] Kotake, S., Udagawa, N., Takahashi, N., Matsuzaki, K., Itoh, K., Ishiyama, S., Saito, S., Inoue, K., Kamatani, N., Gillespie, M.T., Martin, T.J., Suda, T.: "IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis."J.Clin.Invest.. 103. 1345-1352 (1999)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Jimi, E., Akiyama, S., Tsurukai, T., Okahashi, N., Kobayashi, K., Udagawa, N., Nishihara, T., Takahashi, N., Suda T.: "Osteoclast differentiation factor (ODF) acts as a multifunctional regulator in murine osteoclast differentiation and function."J.Immunol.. 163. 434-442 (1999)
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「研究成果報告書概要(欧文)」より
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[Publications] Udagawa, N., Takahashi, N., Jimi, E., Matsuzaki, K., Tsurukai, T., Itoh, K., Nakagawa, N., Yasuda, H., Goto, M., Tsuda, E., Higashio, K., Gillespie, M.T., Martin, T.J., Suda, T.: "Osteoblasts/stromal cells stimulate osteoclast activation through expression of ODF/RANKL but not macrophage colony-stimulating factor."Bone. 25. 517-523 (1999)
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「研究成果報告書概要(欧文)」より
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[Publications] Kobayashi, K., Takahashi, N., Jimi, E., Udagawa, N., Takami, M., Kotake, S., Nakagawa, N., Kinosaki, M., Yamaguchi, K., Shima, N., Yasuda, H., Morinaga, T., Higashio, Martin, T.J., Suda, T.: "Tumor necrosis factor a stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction."J.Exp.Med.. 191. 275-285 (2000)
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「研究成果報告書概要(欧文)」より
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[Publications] Itoh, K., Udagawa, N., Matsuzaki, K., Takami, M., Amano, H., Shinki, T., Ueno, Y., Takahashi, N., Suda, T.: "Importance of membrane-or matrix-associated forms of M-CSF and RANKL/ODF in osteoclastogenesis supported by SaOS-4/3 cells expressing recombinant PTH/PTHrP receptors."J.Bone Miner.Res.. 15. 1766-1775 (2000)
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「研究成果報告書概要(欧文)」より
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[Publications] Udagawa, N., Takahashi, N., Yasuda, H., Mizuno, A., Itoh, K., Ueno, Y., Shinki, T., Gillespie, M.T., Martin, T.J., Higashio, K., Suda, T.: "Osteoprotegerin produced by osteoblasts is an important regulator in osteoclast development and function."Endocrinology. 141. 3478-3484 (2000)
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「研究成果報告書概要(欧文)」より
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[Publications] Takami, M., Takahashi, N., Udagawa, N., Miyaura, C., Suda, K., Woo, J.-T., Martin, T.J., Nagai, K., Suda, T.: "Intracellular calcium and protein kinase C mediate expression of receptor activator of NF-κB ligand (RANKL) and osteoprotegerin in osteoclasts."Endocrinology. 141. 4711-4719 (2000)
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「研究成果報告書概要(欧文)」より
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[Publications] Itoh K, Udagawa N, Katagiri T, Iemura S, Ueno N, Yasuda H, Higashio K, Quinn JMW, Gillespie MT, Martin TJ, Suda T & Takahashi N.: "Bone morphogenetic protein 2 stimulates osteoclast differentiation and survival supported by receptor activator of nuclear factor-κB ligand."Endocrinology. (in press). (2001)
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「研究成果報告書概要(欧文)」より
