Elucidation of the osteoclast-derived cytokine-Wnt signaling network responsible for coupling between bone resorption and formation.
| Project/Area Number |
16H05144
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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 |
General medical chemistry
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| Research Institution | Matsumoto Dental University |
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Principal Investigator |
Takahashi Naoyuki 松本歯科大学, 総合歯科医学研究所, 特任教授 (90119222)
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| Co-Investigator(Kenkyū-buntansha) |
宇田川 信之 松本歯科大学, 歯学部, 教授 (70245801)
小林 泰浩 松本歯科大学, 総合歯科医学研究所, 教授 (20264252)
中村 浩彰 松本歯科大学, 歯学部, 教授 (50227930)
南 康博 神戸大学, 医学研究科, 教授 (70229772)
荒 敏昭 松本歯科大学, 歯学部, 講師 (90387423)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2018: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2017: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Fiscal Year 2016: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
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| Keywords | 破骨細胞 / 骨芽細胞 / カップリング因子 / クラストカイン / スクレロスチン / LIF / HtrA1 / Wnt5a / 骨代謝共役 / Wntシグナル |
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| Outline of Final Research Achievements |
Clastokines secreted by osteoclasts were analyzed. (1) Osteoclasts secreted LIF, which suppressed the secretion of sclerostin by osteocytes. Thus, osteoclasts promoted osteoblastic bone formation through the up-regulation of Wnt-βcatenin signals. (2) W9 peptides suppressed bone resorption activity of osteoclasts and suppressed sclerostin expression by osteocytes. Thus, W9 increased the alveolar bone mass. (3) Osteoclasts abundantly secreted Wnt5a. Wnt5a binds to its receptor, Ror2, which is expressed by osteoclasts. The Wnt5a-Ror2 signal in osteoclasts induced bone-resorbing activity through Daam2→ Rho→ PKN3→ cSrc/Pyk2 signals. (4) Osteoclasts specifically secreted HtrA1, which degraded OPG, suggesting that osteoclasts potentially prepare a microenvironment that is suitable for osteoclastogenesis. Thus, osteoclasts secrete various Clastokines that are involved in bone metabolism.
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| Academic Significance and Societal Importance of the Research Achievements |
従来破骨細胞は骨吸収のみを行う細胞であると考えられてきた。しかし本研究より、破骨細胞は様々なクラストカインを分泌し、骨代謝とりわけ骨代謝共役を担っていることが示された。本研究成果は、破骨細胞がサイトカイン分泌細胞であるあるいは内分泌細胞であるという新しい考え方を示すことができたと考える。さらにLIFの作用を抑制する薬剤、W9ペプチド、HtrA1の阻害剤は特粗鬆症など代謝性骨疾患の治療薬となり得る可能性が示された。
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Report
(4 results)
Research Products
(21 results)
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[Journal Article] Protein kinase N3 promotes bone resorption by osteoclasts in response to Wnt5a-Ror2 signaling.2017
Author(s)
Uehara S, Udagawa N, Mukai H, Ishihara A, Maeda K, Yamashita T, Murakami K, Nishita M, Nakamura T, Kato S, Minami Y, Takahashi N and Kobayashi Y
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Journal Title
Sci Signal
Volume: 10
Issue: 494
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] A Jak1/2 inhibitor, baricitinib, inhibits osteoclastogenesis by suppressing RANKL expression in osteoblasts in vitro.2017
Author(s)
Murakami K, Kobayashi Y, Uehara S, Suzuki T, Koide M, Yamashita T, Nakamura M, Takahashi N, Kato H, Udagawa N and Nakamura Y
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Journal Title
PLOS ONE
Volume: 12
Issue: 7
Pages: e0181126-e0181126
DOI
Related Report
Peer Reviewed / Open Access
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