Mechanisms of Rac1 and Cdc42, Rho small GTPases, in bone and cartilage formation

• Project/Area Number: 24592813
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Functional basic dentistry
• Research Institution: Showa University
• Principal Investigator: ATSUSHI Yamada 昭和大学, 歯学部, 講師 (50407558)
• Co-Investigator(Kenkyū-buntansha): KAMIJO Ryutaro 昭和大学歯学部, 口腔生化学教室, 教授 (70233939)
• Co-Investigator(Renkei-kenkyūsha): AIBA Atsu 東京大学大学院医学系研究科, 附属疾患生命工学センター研究基盤部門・動物資源研究領域, 教授 (20271116)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: コンディショナルノックアウトマウス / 発生学 / 軟骨 / 遺伝子改変マウス / シグナル伝達

Outline of Final Research Achievements

Rac1 and Cdc42 are Rho small GTPases known to regulate multiple cellular functions, including cytoskeletal organization, proliferation, and apoptosis. Recently, their tissue-specific roles have been revealed, especially in mammalian limb development, using limb bud mesenchyme-specific inactivated Rac1 (Rac1fl/fl; Prx1-Cre; Rac1 cKO) and Cdc42 (Cdc421fl/fl; Prx1-Cre; Cdc42 cKO) conditional knockout mice. Both strains demonstrate striking syndactyly of the fore- and hindlimbs. That in Rac1 cKO mice is caused by a failure of interdigital programmed cell death, while syndactyly in Cdc42 cKO mice is caused by not only a failure of interdigital programmed cell death, but also fusion of metacarpals. Also, most of the Cdc42 cKO neonates were viable at birth, though they appeared weaker and no milk was found in their stomachs, and died within a few days. In the present study, we analyzed mechanisms of Rac1 and Cdc42 functions in bone and cartilage formation.

Research Products

• [Journal Article] Cdc42 is critical for cartilage development during endochondral ossification. (2015)
  • Author(s): Suzuki W, Yamada A, Aizawa R, Suzuki D, Kassai H, Harada T, Nakayama M, Nagahama R, Maki K, Takeda S, Yamamoto M, Aiba A, Baba K, Kamijo R
  • Journal Title: Endocrinology Volume: 156 Issue: 1 Pages: 314-322
  • DOI: 10.1210/en.2014-1032
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Strain-rate stiffening of cortical bone: observations and implications from nanoindentation experiments (2014)
  • Author(s): Maruyama N., Shibata Y., Wurihan, Swain M., Kataoka Y., Takiguchi Y., Yamada A., Maki K. and Miyazaki T.
  • Journal Title: Ｎａｎｏｓｃａｌｅ Volume: ６ Issue: 24 Pages: 14863-14871
  • DOI: 10.1039/c4nr03180f
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Porphyromonas gingivalis-derived lysine gingipain enhances osteoclast differentiation induced by tumor necrosis factor and interleukin-1 but suppresses that by interleukin-17: Importance of proteolytic degradation of osteoprotegerin by lysine gingipain. (2014)
  • Author(s): Tomohito Akiyama, Yoichi Miyamoto, Kentaro Yoshimura, Atsushi Yamada, Masamichi Takami, Tetsuo Suzawa, Marie Hoshino, Takahisa Imamura, Chie Akiyama, Rika Yasuhara, Kenji Mishima, Toshifumi Maruyama, Chikara Kohda, Kazuo Tanaka, Jan Potempa, Hisataka Yasuda, Kazuyoshi Baba, Ryutaro Kamijo.
  • Journal Title: J.Biol.Chem. Volume: 289 Issue: 22 Pages: 1-35
  • DOI: 10.1074/jbc.m113.520510
  • Peer Reviewed / Open Access
• [Journal Article] Identification of gene expression profile of neural crest-derived cells isolated from submandibular glands of adult mice (2014)
  • Author(s): Takahashi M, Suzawa T, Yamada A, Yamaguchi T, Mishima K, Osumi N, Maki K, Kamijo R
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 446 Pages: 481-486
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Rho family small G proteins: lessons from tissue-specific gene knockout studies. (2014)
  • Author(s): Yamada A. et al.
  • Journal Title: J Oral Biosci Volume: 56 Pages: 23-29
  • Peer Reviewed
• [Journal Article] Cdc42 plays important roles in bone formation during limb development. (2013)
  • Author(s): Aizawa R. et al.
  • Journal Title: J. Tissue Cult. Dent. Res. Volume: 22(2) Pages: 35-41
  • Peer Reviewed
• [Journal Article] BMP-2 induced expression of Alx3 that is a positive regulator of osteoblast differentiation. (2013)
  • Author(s): Yamada A et al.
  • Journal Title: PLoS ONE Volume: 5(6)
  • Peer Reviewed
• [Journal Article] Octacalcium phosphate suppresses chondrogenic differentiation of ATDC5 cells. (2013)
  • Author(s): Shibuya I. et al.
  • Journal Title: Cell Tissue Res Volume: 352(2) Pages: 401-412
  • Peer Reviewed
• [Journal Article] Downregulation of carbonic anhydrase IX promotes Col10a1 expression in chondrocytes. (2013)
  • Author(s): Maruyama T. et al.
  • Journal Title: PLoS ONE Volume: 8(2)
  • Peer Reviewed
• [Journal Article] The Essential Roles of Small GTPase Rac1 in Limb Development. (2013)
  • Author(s): Suzuki D. et al.
  • Journal Title: J Oral Biosci Volume: 55 Pages: 116-121
  • Peer Reviewed
• [Journal Article] Downregulation of carbonic anhydrase IX promotes Col10a1 expression in chondrocytes (2013)
  • Author(s): Maruyama T, Miyamoto Y, Yamamoto G, Yamada A, Yoshimura K, Suzawa T, Takami M, Akiyama T, Hoshino M, Iwasa F, Ikumi N, Tachikawa T, Mishima K, Baba K, Kamijo R
  • Journal Title: PLoS ONE Volume: Vol.8 Issue: 2 Pages: e56984-e56984
  • DOI: 10.1371/journal.pone.0056984
  • Peer Reviewed
• [Journal Article] Nephronectin expression is regulated by SMAD signaling in osteoblast-like MC3T3-E1 cells (2012)
  • Author(s): Tsukasaki M, Yamada A, Yoshimura K, Miyazono A, Yamamoto M, Takami M, Miyamoto Y, Morimura N, Kamijo R
  • Journal Title: Biochem Biophys Res Commun Volume: 425 Issue: 2 Pages: 390-392
  • DOI: 10.1016/j.bbrc.2012.07.106
  • Peer Reviewed
• [Journal Article] BMP2 differentially regulates the expression of Gremlin1 and Gremlin2, the negative regulators of BMP function, during osteoblast differentiation (2012)
  • Author(s): Suzuki D, Yamada A, Aizawa R, Funato S, Matsumoto T, Suzuki W, Takami M, Miyamoto Y, Suzawa T, Yamamoto M, Baba K, Kamijo R
  • Journal Title: Calcif Tissue Int Volume: 91 Issue: 1 Pages: 88-96
  • DOI: 10.1007/s00223-012-9614-5
  • Peer Reviewed
• [Journal Article] Expression of myelin and lymphocyte protein (MAL) in oral carcinogenesis. (2012)
  • Author(s): Pal SK, Noguchi S, Yamamoto G, Yamada A, Isobe T, Hayashi S, Tanaka J, Tanaka Y, Kamijo R, Yamane GY, Tachikawa T
  • Journal Title: Med Mol Morphol Volume: 45 Issue: 4 Pages: 222-228
  • DOI: 10.1007/s00795-011-0563-2
  • NAID: 10031137147
  • Peer Reviewed
• [Presentation] Oncostatin Mによるネフロネクチン発現制御機構の解明 (2015)
  • Author(s): 黒澤珠希、山田篤、高見正道、鈴木大、守村直子、板部洋之、上條竜太郎
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-27
• [Presentation] Cdc42は口蓋形成過程において必須の遺伝子である。 (2014)
  • Author(s): 中山睦子、山田篤、佐藤友紀、上條竜太郎、槇宏太郎
  • Organizer: 第73回日本矯正歯科学会大会・第５回日韓ジョイントミーティング
  • Place of Presentation: 千葉
  • Year and Date: 2014-10-19
• [Presentation] Cdc42 is essential for cartilage development during endochondral ossification. (2014)
  • Author(s): Wataru Suzuki, Atsushi Yamada, Ryo Aizawa, Dai Suzuki, Shu Takeda, Matsuo Yamamoto, Kazuyoshi Baba, Ryutaro Kamijo
  • Organizer: ANZBMS 24th Annual Scientific Meeting
  • Place of Presentation: New Zealand
  • Year and Date: 2014-09-07
• [Presentation] Cdc42は軟骨分化とそれに続く軟骨内骨化に必須である (2014)
  • Author(s): 鈴木航、山田篤、相澤怜、鈴木大、竹田秀、山本松男、馬場一美、上條竜太郎
  • Organizer: 第32回日本骨代謝学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-07-24
• [Presentation] Rhoファミリー低分子量Gタンパク質Rac1およびCdc42の骨•軟骨形成における機能解析 (2014)
  • Author(s): 山田篤
  • Organizer: 第13回 松本ボーンフォーラム
  • Place of Presentation: 松本
  • Year and Date: 2014-05-10
• [Presentation] マウスリバースジェネティクスによる顎口腔発生制御機構の解明 (2013)
  • Author(s): 山田篤
  • Organizer: 第51回日本口腔組織培養学会設立50周年記念学術大会総会
  • Place of Presentation: 東京
• [Presentation] Small GTPase Cdc42 is essential for cartilage development. (2013)
  • Author(s): Suzuki W. et al
  • Organizer: 91st General Session & Exhibition of the IADR
  • Place of Presentation: Seattle, USA
• [Presentation] 骨軟骨形成の必須因子：Rhoファミリー低分子量Gタンパク質Rac1およびCdc42
  • Author(s): 山田篤
  • Organizer: 第13回東京骨関節フォーラム
  • Place of Presentation: 東京
• [Presentation] 低分子量Gタンパク質Rac1およびCdc42の骨・軟骨形成における機能解析．
  • Author(s): 山田 篤
  • Organizer: 第54回歯科基礎医学会学術集会
  • Place of Presentation: 郡山, 福島
• [Presentation] 低分子量Gタンパク質Cdc42は四肢形成における軟骨分化と肢芽指間部の細胞死に必須である．
  • Author(s): 相澤 怜など
  • Organizer: 第30回日本骨代謝学会学術集会
  • Place of Presentation: 新宿, 東京
• [Book] The New Frontiers in Research for Oral Cancer, Tokyo, MARUZEN. CO. LTD. (2013)
  • Author(s): Yamada A
  • Publisher: Screening for regulators of osteoblast differentiation induced by BMP-2.