Discovery of novel mechanism of BMP/TGF-s signaling inhibition mediatedby Dullard and its regulation of cartilage metabolism

2012 Fiscal Year Final Research Report

• Project/Area Number: 23791628
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Orthopaedic surgery
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: HAYATA Tadayoshi 東京医科歯科大学, 難治疾患研究所, 助教 (40420252)
• Project Period (FY): 2011 – 2012
• Keywords: 軟骨 / BMP / TGF-β

Research Abstract

To investigate roles of Dullard, a BMP/TGF-s signal inhibitor, in cartilage formation, limb- and sternum-specific Dullard knockout (Dullard cKO) mice were generated. Dullard cKO mice showed impairment in ossification. Dullard-deficient chondrocytes showed normal BMP signaling but elevated TGF-s signaling. These results suggest that Dullard regulates endochondral bone formation via suppressing TGF-s signaling.

Research Products

• [Journal Article] Osteoblastic differentiation enhances expression of TRPV4 that is required for calcium oscillation induced by mechanical force (2013)
  • Author(s): Suzuki T, Notomi T, Miyajima D, Mizoguchi F, Hayata T, Nakamoto T, Hanyu R, Kamolratanakul P, Mizuno A, Suzuki M, Ezura Y, Izumi Y, Noda M
  • Journal Title: Bone Volume: 54(1) Pages: 172-8
  • Peer Reviewed
• [Journal Article] Nck1 deficiency accelerates unloading-induced bone loss (2013)
  • Author(s): Aryal S AC, Miyai K, Hayata T, Notomi T, Nakamoto T, Pawson T, Ezura Y, Noda M
  • Journal Title: J Cell Physiol Volume: 228 (7) Pages: 1397-1403
  • Peer Reviewed
• [Journal Article] III.骨研究フロンティア-基礎から臨床まで-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: 最新の骨粗鬆症学-骨粗鬆症の最新知見-日本臨牀 Volume: 71巻増刊号2 Pages: 161-166
• [Journal Article] KDEL tagging: a method for generating dominant-negative inhibitors of the secretion of TGF-beta superfamily proteins (2012)
  • Author(s): Matsukawa S, Moriyama Y, Hayata T, Sasaki H, Ito Y, Asashima M, Kuroda H
  • Journal Title: Int J Dev Biol Volume: 56(5) Pages: 351-6
  • Peer Reviewed
• [Journal Article] Profilin1 regulates sternumdevelopment and endochondral bone formation (2012)
  • Author(s): Miyajima D, Hayata T, Suzuki T, Hemmi H, Nakamoto T, Notomi T, Amagasa T, Bottcher RT, Costell M, Fassler R, Ezura Y, Noda M
  • Journal Title: J Biol Chem Volume: 287(40) Pages: 33545-53
  • Peer Reviewed
• [Journal Article] Anabolic action of parathyroid hormone regulated by the β2-adrenergic receptor (2012)
  • Author(s): Hanyu R, Wehbi VL, Hayata T, Moriya S, Feinstein TN, Ezura Y, Nagao M, Saita Y, Hemmi H, Notomi T, Nakamoto T, Schipani E, Takeda S, Kaneko K, Kurosawa H, Karsenty G, Kronenberg HM, Vilardaga JP, Noda M
  • Journal Title: Proc Natl Acad Sci U S A Volume: 109(19) Pages: 7433-8
  • Peer Reviewed
• [Journal Article] CIZ/NMP4 is expressed in B16 melanoma and forms a positive feedback loop with RANKL to promote migration of the melanoma cells (2012)
  • Author(s): Sakuma T, Nakamoto T, Hemmi H, Kitazawa S, Kitazawa R, Notomi T, Hayata T, Ezura Y, Amagasa T, Noda M
  • Journal Title: J Cell Physiol Volume: 227(7) Pages: 2807-12
  • Peer Reviewed
• [Journal Article] Type VI collagen deficiency induces osteopenia with distortion of osteoblastic cell morphology (2012)
  • Author(s): Izu Y, Ezura Y, Mizoguchi F, Kawamata A, Nakamoto T, Nakashima K, Hayata T, Hemmi H, Bonaldo P, Noda M
  • Journal Title: Tissue Cell Volume: 44(1) Pages: 1-6
  • Peer Reviewed
• [Journal Article] Constitutively active PTH/PTHrP receptor specifically expressed n osteoblasts enhances bone formation induced by bone marrow ablation (2012)
  • Author(s): Ono N, Nakashima K, Schipani E, Hayata T, Ezura Y, Soma K, Kronenberg HM, Noda M
  • Journal Title: J Cell Physiol Volume: 227(2) Pages: 408-15
  • Peer Reviewed
• [Journal Article] 骨のメカノバイオロジー」阻害因子Dullardは、カベオリンープ細胞工学 (2012)
  • Author(s): 野田政樹、江面陽一、早田匡芳、納富拓也、中元哲也、渡辺千穂
  • Journal Title: Smriti Aryal A.C Volume: 31(9) Pages: 1030-32
• [Journal Article] 4.メカニカルストレスによる骨量の制御について (2012)
  • Author(s): 野田政樹、江面陽一、早田匡芳、中元哲也、納富拓也、佐久間朋美、宮嶋大輔、鈴木允文
  • Journal Title: The BONE Volume: 26(2) Pages: 41-46
• [Journal Article] Sympathetic control of bone mass regulated by osteopontin (2011)
  • Author(s): Nagao M, Feinstein TN, Ezura Y, Hayata T, Notomi T, Saita Y, Hanyu R, Hemmi H, Izu Y, Takeda S, Wang K, Rittling S, Nakamoto T, Kaneko K, Kurosawa H, Karsenty G, Denhardt DT, Vilardaga JP, Noda M
  • Journal Title: Proc Natl Acad Sci U S A Volume: 108(43) Pages: 17767-72
  • Peer Reviewed
• [Journal Article] MURF1 deficiency suppresses unloading-induced effects on osteoblasts and osteoclasts to lead to bone loss (2011)
  • Author(s): Kondo H, Ezura Y, Nakamoto T, Hayata T, Notomi T, Sorimachi H, Takeda S, Noda M
  • Journal Title: J Cell Biochem. Volume: 112(12) Pages: 3525-30
  • Peer Reviewed
• [Journal Article] Dok-1 and Dok-2 deficiency induces osteopenia via activation of osteoclasts (2011)
  • Author(s): Kawamata A, Inoue A, Miyajima D, Hemmi H, Mashima R, Hayata T, Ezura Y, Amagasa T, Yamanashi Y, Noda M
  • Journal Title: J Cell Physiol Volume: 226(12) Pages: 3087-93
  • Peer Reviewed
• [Presentation] Functional Analysis of Cnot3 in Regulation of Bone Metabolism (2013)
  • Author(s): Watanabe C, Morita M, Y. Ezura Y, Hayata T, Nakamoto T, Notomi T, Yamamoto M, Noda M, Moriyama K
  • Organizer: International Association for Dental Research General Session
  • Place of Presentation: Seattle, WA, USA
  • Year and Date: 20130320-23
• [Presentation] Cnot3はRANKmRNAの安定性制御を介し骨量維持を行う (2013)
  • Author(s): 渡辺千穂、森田斉弘、江面陽一、中元哲也、早田匡芳、菊口千智、李雪、納富拓也、山本雅、野田政樹、森山啓司
  • Organizer: 日本歯科骨粗鬆症研究会第11回学術大会・総会
  • Place of Presentation: 東京
  • Year and Date: 2013-03-25
• [Presentation] Limb- and Sternum-Specific Inactivation of Dullard Gene Causes Severe Defects in Skeletal Development via Alteration of TGF-s Signaling (Poster Sessions) (2012)
  • 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: Minneapolis, USA
  • Year and Date: 20121012-15
• [Presentation] Chondrocyte Metabolism in Inflammatory Arthritis is regulated by CIZ (Poster Sessions) (2012)
  • Author(s): Nakamoto T, Motoyoshi T, Hada T, Kawasaki M, Sakuma T, Hayata T, Ezura Y, Masaki Noda
  • Organizer: 2012 ASBMR (American Society for Bone and Mineral Research) annual meeting
  • Place of Presentation: Minneapolis, USA
  • Year and Date: 20121012-15
• [Presentation] Cnot3 (Ccr4-not complex subunit3), a Regulator of mRNA Stability, Regulates Bone Mass and Gene Expression Related to Osteoclast Formation (Poster Sessions) (2012)
  • Author(s): Watanabe C, Masahiro Morita M, Ezura Y,Nakamoto T, Hayata T, Notomi T, Moriyama K, Yamamoto T, Noda M
  • Organizer: 2012 ASBMR annual meeting
  • Place of Presentation: Minneapolis, USA
  • Year and Date: 20121012-15
• [Presentation] Identification of Signature Genes Selectively Expressed in Mesenchymal Stem Cells Derived from Synovial Joint Tissues (Poster Sessions) (2012)
  • Author(s): Ezura Y, Hayata T, Nakamoto T, Notomi T,Muneta T, Sekiya I, Noda M
  • Organizer: 2012 ASBMR annual meeting
  • Place of Presentation: Minneapolis, USA
  • Year and Date: 20121012-15
• [Presentation] Nck an Actin Cytoskeleton Modulator, Controls Expression of Osteocytic Genes, Phosphate Homeostasis by Regulating FGF 23 Expression in Bone and Maintains Bone Mass (Poster Sessions) (2012)
  • Author(s): Aryal A.C. S, Miyai K, Ezura Y, Hayata T, Notomi T, Nakamoto T, Pawson T, Noda M
  • Organizer: 2012 ASBMR annual meeting
  • Place of Presentation: Minneapolis, USA
  • Year and Date: 20121012-15
• [Presentation] Parathyroid Hormone Stimulates Tob1 Expression in Osteoblastic Cells in vitro and in vivo (Poster Sessions) (2012)
  • Author(s): Moriya S, Hayata T, Shirakawa J Nakamoto T, Notomi T, Ezura Y, Kaneko K, Noda M
  • Organizer: 2012 ASBMR annual meeting
  • Place of Presentation: Minneapolis,USA
  • Year and Date: 20121012-15
• [Presentation] PTH Enhances Mechanical Stress-induced Osteoblast Proliferation in Calvarial Derived Osteoblasts via Up-regulation of CyclinD1 Expression (Poster Sessions) (2012)
  • Author(s): Shirakawa J, Ezura Y, Notomi T, Hayata T, Nakamoto T, Moriya S, Omura K, Noda M
  • Organizer: 2012 ASBMR annual meeting
  • Place of Presentation: Minneapolis, USA
  • Year and Date: 20121012-15
• [Presentation] TGF-β1 Decreases Ift88 Expression in Chondrocytic Cell Line ATDC5 (Poster Sessions) (2012)
  • Author(s): Kawasaki M, Nakamoto T, Notomi T, Hayata T, Ezura Y, Noda M
  • Organizer: 2012 ASBMR annual meeting
  • Place of Presentation: Minneapolis, USA
  • Year and Date: 20121012-15
• [Presentation] Analysis of high turnover type bone loss due to haploinsufficiency of Cnot3, a subunit of Ccr4-not complex (mRNA deadenylase) (2012)
  • Author(s): Watanabe C, Ezura Y, Nakamoto T, Hayata T, Notomi T, Moriyama K, Noda M
  • Organizer: 1st Asia-Pacific Bone and Mineral Research Meeting with the ANZBMS (Australia & New Zeala d Bone & Mineral Society) 22nd Annual Scientific Meeting
  • Place of Presentation: Perth
  • Year and Date: 20120902-05
• [Presentation] 四肢及び胸骨特異的Dullard遺伝子欠損マウスは骨化遅延を示す (2012)
  • Author(s): 早田匡芳、江面陽一、野田政樹
  • Organizer: 第30回日本骨代謝学会
  • Place of Presentation: 東京
  • Year and Date: 20120719-21
• [Presentation] Deficiency of Nck, an Actin Cytoskeleton Modulator in the Osteoblast Inhibits Osteoblast Migration and Suppresses Bone Formation (2012)
  • Author(s): Aryal A.C. S, Miyai K, Ezura Y, Hayata T, Notomi T, Nakamoto T, Pawson T, Noda M
  • Organizer: 第30回日本骨代謝学会
  • Place of Presentation: 東京
  • Year and Date: 20120719-21
• [Presentation] 骨量制御の新転写後性分子機構:mRNAdeadenylaseであるCcr4-not complex構成因子Cnot3の欠失による高回転型の骨量減少の解析 (2012)
  • Author(s): 渡辺千穂、江面陽一、中元哲也、早田匡芳、納富拓也、森山啓司、野田政樹
  • Organizer: 第30回日本骨代謝学会
  • Place of Presentation: 東京
  • Year and Date: 20120719-21
• [Presentation] 一次繊毛タンパクBbs3は骨代謝に関与する (2012)
  • Author(s): 川崎真希理、中元哲也、納富拓也、早田匡芳、江面陽一、野田政樹
  • Organizer: 第30回日本骨代謝学会
  • Place of Presentation: 東京
  • Year and Date: 20120719-21
• [Presentation] 骨芽細胞におけるGタンパク質共役型受容体(GPCR)によるRANKL制御の検討 (2012)
  • Author(s): 守屋秀一、早田匡芳、中元哲也、納富拓也、江面陽一、金子和夫、野田政樹
  • Organizer: 第30回日本骨代謝学会
  • Place of Presentation: 東京
  • Year and Date: 20120719-21
• [Presentation] ヒト骨髄および滑膜由来間葉系細胞において異なるCpGメチル化を示す遺伝子群の探索と骨軟骨細胞分化の制御に関わる転写因子群の抽出:RUNX2およびRUNX3,DLX5,ALX4遺伝子 (2012)
  • Author(s): 江面陽一、早田匡芳、中元哲也、納富拓也、関谷一郎、宗田大、野田政樹
  • Organizer: 第30回日本骨代謝学会
  • Place of Presentation: 東京
  • Year and Date: 20120719-21
• [Presentation] PTHの骨形成促進作用はシャトリングタンパク質CIZによって抑制される (2012)
  • Author(s): 中元哲也、平林恭子、AlexandeValentinitsch、川崎真希理、佐久間朋美、早田匡芳、江面陽一、Ernestina Schipani、Henry M. Kronenberg、野田政樹
  • Organizer: 第30回日本骨代謝学会
  • Place of Presentation: 東京
  • Year and Date: 20120719-21
• [Presentation] PTH及びメカニカルストレスによる骨芽細胞におけるサイクリンD1発現の検討 (2012)
  • Author(s): 白川純平、江面陽一、中元哲也、早田匡芳、納富拓也、小村健、野田政樹
  • Organizer: 第30回日本骨代謝学会
  • Place of Presentation: 東京
  • Year and Date: 20120719-21
• [Presentation] Limb- and sternum-specific inactivation of Dullard gene causes severe defects in skeletal development via alteration of TGF-s signaling (2012)
  • Author(s): Hayata T, Ezura Y and Noda M
  • Organizer: Australian & New Zealand Bone& Mineral Society 22nd Annual Scientific Meeting in conjunction with 1st Asia-Pacific Bone and Mineral Research meeting
  • Place of Presentation: Perth, Australia
  • Year and Date: 2012-09-25
• [Presentation] Cnot3 (Ccr4-not complex subunit 3) controls bone mass via regulating expression of genes including those related to osteoclastic activity (2012)
  • Author(s): Watanabe C, Morita M, Ezura Y, Nakamoto T, Hayata T, Notomi T, Yamamoto T, Moriyama K, Noda M
  • Organizer: The 2nd Tri-university Consortium on Oral Science and Education
  • Place of Presentation: Beijing, China
  • Year and Date: 2012-07-27
• [Presentation] Dullard is a novel common negative regulator of BMP signaling in osteoblasts and chondrocytes acting at Smad1 level independently ofcaveolae-proteasome pathway (2011)
  • Author(s): Hayata T, Ezura Y, Asashima M, Nishinakamura R, Noda M
  • Organizer: The 33rdAnnual Meeting of American Society for Bone Mineral and Research
  • Place of Presentation: San Diego, USA
  • Year and Date: 20110916-20
• [Presentation] Sympathetic Control of BoneMass Regulated By Osteopontin (2011)
  • Author(s): Nagao M, Saita Y, Hanyu R, Hayata T, Nakamoto T, Izu Y, Notomi T, Takeda S,Karsenty G, Rittling S, Ezura Y, Vilardaga,JP, Noda M
  • Organizer: ASBMR 2011 Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 20110916-20
• [Presentation] Expression of Ift88, a Cilia ComponentGene, Is Under Temporal Regulation Alongwith the Differentiation of Chondrocytic Cell Line ATDC5 (2011)
  • Author(s): Kawasaki M, Nakamoto T, Notomi T,Hayata T, Ezura Y, M. Noda M
  • Organizer: ASBMR 2011 AnnualMeeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 20110916-20
• [Presentation] TRPV4 Deficiency Suppresses Fluid Flow Induced Activation of Calcium Oscillation in a Manner Dependent on Osteoblastic Differentiation (2011)
  • Author(s): Suzuki T, Notomi T, Miyajima D, Ezura Y, Nakamoto T, Hayata T, Mizuno A, Suzuki M, Mizoguchi F, Izumi Y, Noda M
  • Organizer: ASBMR 2011 Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 20110916-20
• [Presentation] Role of CIZ in Melanoma Activity for Metastasis (2011)
  • Author(s): Sakuma T, Hemmi H, Notomi T, Nakamoto T, Hayata T, Ezura Y, Noda M
  • Organizer: ASBMR 2011 Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 20110916-20
• [Presentation] Molecular mechanism of CIZ actions to exacerbate inflammation in serum-induced arthritis based on formation of positive feedback loop with IL-1 beta (2011)
  • Author(s): Nakamoto T, Motoyoshi T, Kawasaki M, Sakuma T, Hayata T, Ezura Y, M. Noda M
  • Organizer: ASBMR 2011 Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 20110916-20
• [Presentation] Identification of the Differentially Methylated Promoter and Intragenic CpG-Cytosines in the Human Synovium and Bone Marrow Derived Mesenchymal Stem Cells (2011)
  • Author(s): Ezura Y, Hayata T, Nakamoto T, Notomi T, Sekiya I, Muneta T, Noda M
  • Organizer: ASBMR 2011 Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 20110916-20
• [Presentation] Cnot3, a crucial factor of mRNA stability, controls osteoblastic differentiation. The American Society for Bone and Mineral Research (2011)
  • Author(s): Watanabe C, Morita M, Ezura Y, Nakamoto T, Hayata T, Hemmi H, Notomi T, Moriyama K, Yamamoto T, Noda M
  • Organizer: (ASBMR) 2011 Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 20110916-20
• [Presentation] Conditional Profilin1 Deficiency in Multiple Cell Linages of Mesenchyme Origin Based on Prx1-Cre System Severely Disrupts Axial and Appendicular Skeletal Development (2011)
  • Author(s): Miyajima D, Hayata T, Suzuki T, Ezura Y, Nakamoto T, Notomi T, Amagasa T, Bottcher RT, Fassler R, Noda1 M
  • Organizer: ASBMR 2011 Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 20110916-20
• [Presentation] Actin Cytoskeleton Protein, Supports Osteoblastic Bone Increment and Suppresses Osteoclastic Bone Loss (2011)
  • Author(s): Aryal S, Miyai K, Ezura Y, Hayata T, Nakamoto T, Pawson T, Noda M. Nck
  • Organizer: ASBMR 2011 Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 20110916-20
• [Presentation] Inactivation of Dullard in the mouse limb and sternum displays retardation of ossification in skeletogenesis (2011)
  • Author(s): Hayata T, Ezura Y, Asashima M, Nishinakamura R, Noda M
  • Organizer: KEY Forum in Developmental Biology and RegenerativeMedicine- Supported by Global COE andIMEG
  • Place of Presentation: Kumamoto University
  • Year and Date: 20110908-09
• [Presentation] 四肢-胸骨特異的Dullardロテアソーム経路とは独立にBMPシグナルを抑制する (2011)
  • Author(s): 早田匡芳、江面陽一、西中村隆一、浅島誠、野田政樹
  • Organizer: 第29回日本骨代謝学会
  • Place of Presentation: 大阪
  • Year and Date: 20110728-30
• [Presentation] BMP阻害因子Dullardは、カベオリンープロテアソーム経路とは独立にBMPシグナルを抑制する (2011)
  • Author(s): 早田匡芳、江面陽一、野田政樹
  • Organizer: 第29回日本骨代謝学会
  • Place of Presentation: 大阪
  • Year and Date: 20110728-30
• [Presentation] mRNA制御因子であるCnot3 は骨量制御に関与する (2011)
  • Author(s): 渡辺千穂、森田斉弘、江面陽一、中元哲也、早田匡芳、辺見弘明 、納富拓也,森山啓司、山本雅、野田政樹
  • Organizer: 第29回日本骨代謝学会
  • Place of Presentation: 大阪
  • Year and Date: 20110728-30
• [Presentation] TRPV4はメカニカルストレス下での骨芽細胞におけるカルシウムイオン流入を延長する (2011)
  • Author(s): 鈴木允文、納富拓也、溝口史高、宮嶋大輔、早田匡芳、中元哲也、江面陽一、和泉雄一、野田政樹
  • Organizer: 第29回日本骨代謝学会
  • Place of Presentation: 大阪
  • Year and Date: 20110728-30
• [Presentation] CIZとIL-1βは相互に発現を誘導し、関節炎に関与する (2011)
  • Author(s): 中元哲也、元吉貴之、川崎真希理、佐久間朋美、早田匡芳、江面陽一、野田政樹
  • Organizer: 第29回日本骨代謝学会
  • Place of Presentation: 大阪
  • Year and Date: 20110728-30
• [Presentation] エーラースダンロス症候群「古典型」のモデル実験系として知られる5型コラーゲンα1鎖遺伝子へテロ欠損マウスの骨形態解析 (2011)
  • Author(s): 江面陽一、納富拓也、早田匡芳、中元哲也、Richard J. Wenstrup、David E.Birk、野田政樹
  • Organizer: 第29回日本骨代謝学会
  • Place of Presentation: 大阪
  • Year and Date: 20110728-30
• [Remarks] 1.「骨粗鬆症の為の骨を作るメカニズムの発見」2012年4月24日。東京医科歯科大学プレスリリース。
  • URL: http://www.tmd.ac.jp/press-release/20120419/index.html
• [Remarks] 2.「骨粗鬆症における交感神経作用のメカニズムの解明」2011年10月11日。東京医科歯科大学プレスリリース。
  • URL: http://www.tmd.ac.jp/press-release/20111011/index.html