Elucidation of pathogenic mechanism of arthrogryposis multiplex congenita by Ctdnep1 gene deficiency

• Project/Area Number: 25462287
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: University of Tsukuba (2015); Tokyo Medical and Dental University (2013)
• Principal Investigator: Hayata Tadayoshi 筑波大学, 医学医療系, 准教授 (40420252)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: BMP / TGF-β / 筋肉 / 軟骨 / 筋・骨格形成 / TGF-beta

Outline of Final Research Achievements

In order to investigate the role of Ctdnep1 for musculoskeletal and joint development, we generated limb- and sternum-specific knockout mice (Ctdnep1 cKO). Ctdnep1 cKO mice showed joint contracture and impaired walking. Histological analysis showed that joint structure was formed normally, but development of muscle fiber was severely affected and chondrocytes of proximal femur proliferated abnormally. Cell culture experiments showed that TGF-β signaling was increased and BMP signaling was decreased in the absence of Ctdnep1. These results suggest that Ctdnep1 maintain BMP signaling by suppressing TGF-β signaling in muscle system and plays crucial role in muscle development.

Research Products

• [Journal Article] Mice Deficient in CIZ/NMP4 Develop an Attenuated Form of K/BxN-Serum Induced Arthritis. (2016)
  • Author(s): Nakamoto T, Izu Y, Kawasaki M, Notomi T, Hayata T, Noda M, Ezura Y.
  • Journal Title: J Cell Biochem. Volume: 117 Issue: 4 Pages: 970-977
  • DOI: 10.1002/jcb.25382
  • Peer Reviewed / Open Access
• [Journal Article] Nck influences preosteoblastic/osteoblastic migration and bone mass (2015)
  • Author(s): Aryal Smriti, Kentaro Miyai, Yayoi Izu, Tadayoshi Hayata, Takuya Notomi, Masaki Noda, Yoichi Ezura
  • Journal Title: Proc Natl Acad Sci USA Volume: 112 Issue: 50 Pages: 15432-7
  • DOI: 10.1073/pnas.1518253112
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] TGF-Beta Suppresses Ift88 Expression in Chondrocytic ATDC5 Cells. (2015)
  • Author(s): Kawasaki, M., Ezura, Y., Hayata, T., Notomi, T., Izu, Y., and Noda, M.
  • Journal Title: Journal of Cellular Physiology Volume: - Issue: 11 Pages: 2788-95
  • DOI: 10.1002/jcp.25005
  • Peer Reviewed / Open Access
• [Journal Article] β2 Adrenergic receptor activation suppresses BMP-induced alkaline phosphatase expression in osteoblast-like MC3T3E1 cells. (2015)
  • Author(s): Yamada, T., Ezura, Y., Hayata, T., Moriya, S., Shirakawa, J., Notomi, T., Arayal, S., Kawasaki, M., Izu, Y., Harada, K., and Noda, M.
  • Journal Title: Journal of Cellular Biochemistry Volume: 116 Issue: 6 Pages: 1144-52
  • DOI: 10.1002/jcb.25071
  • Peer Reviewed / Open Access
• [Journal Article] PTH regulates β2-adrenergic receptor expression in osteoblast-like MC3T3-E1 cells. (2015)
  • Author(s): Moriya, S., Hayata, T., Notomi, T., Aryal, S., Nakamaoto, T., Izu, Y., Kawasaki, M., Yamada, T., Shirakawa, J., Kaneko, K., Ezura, Y., and Noda, M.
  • Journal Title: Journal of Cellular Biochemistry Volume: 116 Issue: 1 Pages: 142-148
  • DOI: 10.1002/jcb.24953
  • Peer Reviewed / Open Access
• [Journal Article] Dullard/Ctdnep1 regulates endochondral ossification via suppression of TGF-β signaling. (2015)
  • Author(s): Hayata T, Ezura Y, Asashima M, Nishinakamura R, Noda M.
  • Journal Title: J Bone Miner Res Volume: 30 Issue: 2 Pages: 318-29
  • DOI: 10.1002/jbmr.2343
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 再生医療と幹細胞 (2015)
  • Author(s): 早田匡芳、浅島誠
  • Journal Title: 日本臨牀 Volume: 1080 Pages: 40-46
• [Journal Article] Hindlimb-unloading suppresses B cell population in the bone marrow and peripheral circulation associated with OPN expression in circulating blood cells. (2014)
  • Author(s): Ezura Y1, Nagata J, Nagao M, Hemmi H, Hayata T, Rittling S, Denhardt DT, Noda M.
  • Journal Title: J Bone Miner Metab. Volume: 33 Issue: 1 Pages: 48-54
  • DOI: 10.1007/s00774-014-0568-8
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Stability of mRNA influences steoporotic bone mass via CNOT3 (2014)
  • Author(s): Watanabe, C. Morita, M. Yamamoto T. (13名)
  • Journal Title: Natl Acad Sci U S A Volume: Vol.111 Issue: 7 Pages: 2692-2697
  • DOI: 10.1073/pnas.1316932111
  • Peer Reviewed / Open Access
• [Journal Article] Osteoblastic differentiation enhances expression of TRPV4 that is required for calcium oscillation induced by mechanical force (2013)
  • Author(s): Takafumi Suzuki
  • Journal Title: Bone Volume: 54(1) Issue: 1 Pages: 172-8
  • DOI: 10.1016/j.bone.2013.01.001
  • Peer Reviewed
• [Journal Article] Nck1 Deficiency Accelerates Unloading-Induced Bone Loss (2013)
  • Author(s): Aryal A. C. S, Miyai K, Hayata T, Notomi T, Nnakamoto T, Pawson T, Ezura Y, Noda M.
  • Journal Title: Journal of Cellular Physiology Volume: 228 Issue: 7 Pages: 1397-403
  • DOI: 10.1002/jcp.24317
  • Peer Reviewed
• [Journal Article] 骨形成・骨吸収における関連因子の働き PTH (2013)
  • Author(s): 野田政樹、江面陽一、早田匡芳、守屋秀一、白川純平、Smriti Aryal、納富拓也、渡辺千穂、長尾雅史、羽生亮
  • Journal Title: 日本臨牀 Volume: 71 Pages: 161-163
• [Presentation] Dullard/Ctdnep1遺伝子は、TGF-βシグナルの抑制を介して、内軟骨性骨化を制御する (2016)
  • Author(s): 早田匡芳、江面陽一、浅島誠、西中村隆一、野田政樹
  • Organizer: 第29回日本軟骨代謝学会
  • Place of Presentation: 広島市広島大学広仁会館
  • Year and Date: 2016-02-19
  • Invited
• [Presentation] Negative regulation of TGF-β signaling by Dullard is required for endochondral ossification. (2015)
  • Author(s): Hayata T, Ezura Y, Asashima M, Nishinakamura R, Noda M
  • Organizer: 12th Bone Biology Forum
  • Place of Presentation: 千葉県幕張市クロス・ウェーブ幕張
  • Year and Date: 2015-08-21
  • Int'l Joint Research
• [Presentation] 脱リン酸化酵素Dullard/Ctdnep1は、TGF-βシグナルの抑制を介してマウス内軟骨性骨化を制御する。 (2015)
  • Author(s): 早田匡芳、江面陽一、浅島誠、西中村隆一、野田政樹
  • Organizer: 第１回日本骨免疫学会
  • Place of Presentation: 沖縄県宮古市ホテルブリーズベイマリーナ
  • Year and Date: 2015-06-30
• [Presentation] Dullard/Ctdnep1 regulates endochondral ossification via suppression of TGF-β signaling. (2015)
  • Author(s): Hayata T, Ezura Y, Asashima M, Nishinakamura R, Noda M
  • Organizer: 13th Congress of the International Society of Bone Morphometry
  • Place of Presentation: 東京都文京区ホテルガーデンパレス
  • Year and Date: 2015-04-27
  • Int'l Joint Research
• [Presentation] Dullard prevents excessive TGF-beta signaling in skeleton. (2013)
  • Author(s): Hayata T, Ezura Y, Asashima M, Nishinakamura R, Noda M.
  • Organizer: The 3rd international symposium by JSPS Core-to-Core Program “Cooperative International Framework in TGF-beta Family Signaling”
  • Place of Presentation: 愛媛県松山市
• [Presentation] Dullard/Ctdnep1 regulates endochondral bone formation through limiting TGF-beta signaling. (2013)
  • Author(s): Hayata T, Ezura Y, Asashima M, Nishinakamura R, Noda M.
  • Organizer: American Society for Bone Mineral and Research annual meeting
  • Place of Presentation: Baltimore, USA
• [Presentation] Dullard gene regulates endochondral bone formation via suppression of TGF-beta signaling during skeletal development. (2013)
  • Author(s): Hayata T, Ezura Y, Asashima M, Nishinakamura R, Noda M.
  • Organizer: The 8th International Symposium of the Institute Network & The Symposium of the Research Core for Transdisciplinary Collaboration on Tissue Engineering and Regenerative Medicine
  • Place of Presentation: 京都府京都市
• [Presentation] Dullard gene regulates endochondral bone formation via suppression of TGF-beta signaling during skeletal development. (2013)
  • Author(s): Hayata T, Ezura Y, Nishinakamura R, Asashima M, Noda M.
  • Organizer: 2nd Joint Meeting of the International Bone and Mineral Society and The Japanese Society for Bone and Mineral Research
  • Place of Presentation: 兵庫県神戸市
• [Presentation] Dullard/Ctdnep1は、TGF-betaシグナルの抑制を介して内軟骨性骨化を制御する。 (2013)
  • Author(s): 早田匡芳、江面陽一、浅島誠、西中村隆一、野田政樹
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 兵庫県神戸市
• [Remarks] 筑波大学医学医療系生体シグナル制御学研究室
  • URL: https://www.facebook.com/biological.signaling.regulation/
• [Remarks] 早田匡芳准教授（生命医科学域・生体シグナル制御学）が第21回日本軟骨代謝学会賞を受賞しました
  • URL: http://www.md.tsukuba.ac.jp/top/topics/160127.html
• [Remarks] 骨粗鬆症を抑制する新しい分子機能の発見
  • URL: http://www.tmd.ac.jp/press-release/20140204/index.html