Elucidation of roles of Dullard, a BMP signal inhibitor in bone formation

2010 Fiscal Year Final Research Report

• Project/Area Number: 21791386
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Orthopaedic surgery
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: HAYATA Tadayoshi Tokyo Medical and Dental University, 難治疾患研究所, 助教 (40420252)
• Research Collaborator: 江面 陽一 東京医科歯科大学, 難治疾患研究所, 助教 (50333456) ; 野田 政樹 東京医科歯科大学, 難治疾患研究所, 助教 (50231725) ; 西中村 隆一 熊本大学, 発生医学研究所, 教授 (70291309) ; 浅島 誠 東京大学, 大学院・総合文化研究科, 名誉教授 (00090564)
• Project Period (FY): 2009 – 2010
• Keywords: 骨芽細胞 / 骨形成 / BMP / TGF-β

Research Abstract

Bone morphogenetic protein (BMP) plays crucial roles in skeletal formation, and its signal level is regulated properly by negative regulators. In the present study, I investigated involvement of novel BMP inhibitor Dullard in bone formation. I found that Dullard is localized in intracellular membrane structure, expressed in osteoblast, and suppress BMP signaling at least at intracellular signal transducer Smad1 level.

Research Products

• [Journal Article] Osteopontin deficiency enhances parathyroid hormone/parathyroid hormone related peptide receptor (PPR) signaling-induced alteration in tooth formation and odontoblastic morphology. (2011)
  • Author(s): Morishita M, Ono N, Miyai K, Nakagawa T, Hanyu R, Nagao M, Kamolratanakul P, Notomi T, Rittling SR, Denhardt DT, Kronenberg HM, Ezura Y, Hayata T, Nakamoto T, Noda M.
  • Journal Title: Tissue Cell. 43(3) Pages: 196-200
  • Peer Reviewed
• [Journal Article] Per-1 is a specific clock gene regulated by parathyroid hormone (PTH) signaling in osteoblasts and is functional for the transcriptional events induced by PTH. (2011)
  • Author(s): Hanyu R, Hayata T, Nagao M, Saita Y, Hemmi H, Notomi T, Nakamoto T, Schipani E, Knonenbery H, Kaneko K, Kurosawa H, Ezura Y, Noda M.
  • Journal Title: J Cell Biochem. 112(2) Pages: 433-438
  • Peer Reviewed
• [Journal Article] Nanogel-based scaffold delivery of prostaglandin E(2) receptor-specific agonist in combination with a low dose of growth factor heals critical-size bone defects in mice. (2011)
  • Author(s): Kamolratanakul P, Hayata T, Ezura Y, Kawamata A, Hayashi C, Yamamoto Y, Hemmi H, Nagao M, Hanyu R, Notomi T, Nakamoto T, Amagasa T, Akiyoshi K, Noda M.
  • Journal Title: Arthritis Rheum. 63(4) Pages: 1021-1033
  • Peer Reviewed
• [Journal Article] Schnurri-2 deficiency counteracts against bone loss induced by ovariectomy. (2011)
  • Author(s): Nagao M, Saita Y, Hanyu R, Hemmi H, Notomi T, Hayata T, Nakamoto T, Nakashima K, Kaneko K, Kurosawa H, Ishii S, Ezura Y, Noda M.
  • Journal Title: J Cell Physiol. 226(3) Pages: 573-578
  • Peer Reviewed
• [Journal Article] Control of bone remodeling by nervous system.Nervous system and bone. (2010)
  • Author(s): Noda M, Nagao M, Hanyu R, Mizoguchi F, Notomi T, Hayata T, Nakamoto T, Ezura Y.
  • Journal Title: Clin Calcium. 20(12) Pages: 1801-1805
• [Journal Article] Osteoclast-specific Dicer gene deficiency suppresses osteoclastic bone resorption. (2010)
  • Author(s): Mizoguchi F, Izu Y, Hayata T, Hemmi H, Nakashima K, Nakamura T, Kato S, Miyasaka N, Ezura Y, Noda M.
  • Journal Title: J Cell Biochem. 109(5) Pages: 866-875
  • Peer Reviewed
• [Journal Article] Combinatory effects of androgen receptor deficiency and hind limb unloading on bone. (2009)
  • Author(s): Saita Y, Nakamura T, Mizoguchi F, Nakashima K, Hemmi H, Hayata T, Ezura Y, Kurosawa H, Kato S, Noda M.
  • Journal Title: Horm Metab Res. 41(11) Pages: 822-828
  • Peer Reviewed
• [Journal Article] Osteoblastic bone formation is induced by using nanogel-crosslinking hydrogel as novel scaffold for bone growth factor. (2009)
  • Author(s): Hayashi C, Hasegawa U, Saita Y, Hemmi H, Hayata T, Nakashima K, Ezura Y, Amagasa T, Akiyoshi K, Noda M.
  • Journal Title: J Cell Physiol. 220(1) Pages: 1-7
  • Peer Reviewed
• [Journal Article] ANA deficiency enhances bone morphogenetic protein-induced ectopic bone formation via transcriptional events. (2009)
  • Author(s): Miyai K, Yoneda M, Hasegawa U, Toita S, Izu Y, Hemmi H, Hayata T, Ezura Y, Mizutani S, Miyazono K, Akiyoshi K, Yamamoto T, Noda M.
  • Journal Title: J Biol Chem. 284(16) Pages: 10593-10600
  • Peer Reviewed
• [Presentation] CIZは悪性黒色腫細胞の転移に促進的に働く (2010)
  • Author(s): 佐久間朋美、中元哲也、宮井健太郎、辺見弘明、天笠光雄、早田匡芳、江面陽一、野田政樹
  • Organizer: 第33回日本分子生物学会
  • Place of Presentation: 神戸
  • Year and Date: 20101207-20101210
• [Presentation] 新規BMP阻害因子Dullardは、骨芽細胞においてBMP受容体及びSmad1の下流でBMP 応答性の転写を抑制する (2010)
  • Author(s): 早田匡芳、江面陽一、西中村隆一、浅島誠、野田政樹
  • Organizer: 第33回日本分子生物学会年会
  • Place of Presentation: 神戸
  • Year and Date: 20101206-20101210
• [Presentation] Ovariectomy induced bone loss was prevented by the deficiency of jund which determines osteoblastic activity and basal levels of bone mass (2010)
  • Author(s): Kawamata A, Yokoyama H, Izu Y, Hayata T, Wanger EF, Nakashima K, Ezura Y, Noda M, Amagasa T.
  • Organizer: The 9^<th> Asian Congress on Oral and Maxillofacial Surgery
  • Place of Presentation: Kuala Lumpur
  • Year and Date: 20101125-20101128
• [Presentation] Dullard, a Novel BMP Inhibitor, Targets Smad1 to Suppress BMP-dependent Transcription in Mammalian Osteoblastic Cells. (2010)
  • Author(s): Hayata T, Ezura Y, Asashima M, Nishinakamura R, Noda M.
  • Organizer: The 32th Annual Meeting of the American Society for Bone Mineral and Research
  • Place of Presentation: Toronto, Canada.
  • Year and Date: 20101015-20101019
• [Presentation] Adrenergic Receptor Regulates Anabolic Action of Constitutively Active Form of PTH/PTHrP Receptor Signaling. (2010)
  • Author(s): Hanyu R, Hayata T, Nakamoto T, Notomi T, Henry Kronenberg, Saita Y, Hemmi H, Nagao M, Ezura Y, Shu Takeda, Noda M.
  • Organizer: The 32th Annual Meeting of the American Society for Bone Mineral and Research
  • Place of Presentation: Toronto, CANADA.
  • Year and Date: 20101015-20101019
• [Presentation] CIZ Expression is Enhanced by Inflammatory Stimulation and Transcriptionally Regulates the RANKL Promoter. (2010)
  • Author(s): Nakamoto T, Sakuma T, Motoyoshi T, Hada T, Hayata T, Ezura Y, Kitazawa R, Kitazawa S, Noda M.
  • Organizer: The 32th Annual Meeting of the American Society for Bone Mineral and Research
  • Place of Presentation: Toronto, CANADA.
  • Year and Date: 20101015-20101019
• [Presentation] Cnot3, a Novel Critical Regulator of a mRNA Stability, is Involved in the Maintenance of the Bone Mass and the Bone Structure in Senile Osteoporosis Model. (2010)
  • Author(s): Watanabe C, Morita M, Ezura Y, Nakamoto T, Hayata T, Hemmi H, Notomi T, Moriyama K, Yamamoto T, Noda M.
  • Organizer: The 32th Annual Meeting of the American Society for Bone Mineral and Research
  • Place of Presentation: Toronto, CANADA.
  • Year and Date: 20101015-20101019
• [Presentation] Deficiency of Dok-1 and Dok-2, Ras-Erk Pathway Inhibitors, Enhances Bone Loss in Postmenopausal Osteoporosis Model of Mice. (2010)
  • Author(s): Miyajima D, Kawamata A, Inoue A, Ezura Y, Nakamoto T, Hayata T, Notomi T, Amagasa T, Yamanashi Y, Noda M.
  • Organizer: The 32th Annual Meeting of the American Society for Bone Mineral and Research
  • Place of Presentation: Toronto, CANADA.
  • Year and Date: 20101015-20101019
• [Presentation] Identification of Novel Molecule for Melanoma Malignancy -Role of CIZ- (2010)
  • Author(s): Sakuma T, Hayata T, Miyai K, Noda M, Ezura Y.
  • Organizer: The 32th Annual Meeting of the American Society for Bone Mineral and Research
  • Place of Presentation: Toronto, CANADA.
  • Year and Date: 20101015-20101019
• [Presentation] Nck1, a Molecular Adaptor Prerequisite for Cell Motility, is Stimulated by Bone Morphogenetic Protein and Contributes to Maintain Bone Mass. (2010)
  • Author(s): Aryal AC S, Hanyu R, Nakamoto T, Miyai K, Nagao M, Ezura Y, Hayata T, Notomi T, Hemmi H, Pawson T, Noda M. Nckl
  • Organizer: The 32th Annual Meeting of the American Society for Bone Mineral and Research
  • Place of Presentation: Toronto, CANADA.
  • Year and Date: 20101015-20101019
• [Presentation] Osteopontin Plays a Pivotal Role in Sympathetic Control of Bone Mass. (2010)
  • Author(s): Nagao M, Ezura Y, Saita Y, Nakamoto T, Hayata T, Izu Y, Hanyu R, Hemmi H, Notomi T, Rittling S, Kurosawa H, Kaneko K, Denhardt D, Noda M.
  • Organizer: The 32th Annual Meeting of the American Society for Bone Mineral and Research
  • Place of Presentation: Toronto, CANADA.(口頭発表)
  • Year and Date: 20101015-20101019
• [Presentation] PTH Anabolic Action is Influenced by the Deficiency of TRPV4 in Bone. (2010)
  • Author(s): Kamolratanakul P, Ezura Y, Mizoguchi F, Hayata T, Hemmi H, Notomi T, Amagasa T, Noda M.
  • Organizer: The 32th Annual Meeting of the American Society for Bone Mineral and Research
  • Place of Presentation: Toronto, CANADA.
  • Year and Date: 20101015-20101019
• [Presentation] Schnurri2 Deficiency Increases all of 1,25(OH)2D3, Renal 25-hydroxyvitamin D 1-α Hydroxylase, PTH, FGF23, Serum Calcium and Phosphate in Association with Hypercalcification in Joints. (2010)
  • Author(s): Nagao M, Ezura Y, Saita Y, Miyai K, Hanyu R, Nakamoto T, Hemmi H, Hayata T, Notomi T, Ishii S, Kato S, Fukumoto S, Kurosawa H, Kaneko K, Noda M.
  • Organizer: The 32th Annual Meeting of the American Society for Bone Mineral and Research
  • Place of Presentation: Toronto, CANADA.(口頭発表)
  • Year and Date: 20101015-20101019
• [Presentation] TRPV4 (Transient Receptor Potential Vanilloid 4), a Mechanosensor for Bone Is Required for the Maintenance of Bone Mineral Density of Mandible Exposed to Occlusal Force. (2010)
  • Author(s): Suzuki T, Notomi T, Ezura Y, Nakamoto T, Hayata T, Hemmi H, Mizuno A, Suzuki M, Mizoguchi F, Y Izumi, Noda M.
  • Organizer: The 32th Annual Meeting of the American Society for Bone Mineral and Research
  • Place of Presentation: Toronto, CANADA.
  • Year and Date: 20101015-20101019
• [Presentation] Unloading-induced Suppression of B-lymphogenesis and Expansion of Peripheral Monocyte/macrophage Lineage Cells is Preserved in the Mice Deficient for Osteopontin. (2010)
  • Author(s): Ezura Y, Nagata J, Hemmi H, Nagao M, Notomi T, Hayata T, Nakamoto T, Noda M.
  • Organizer: The 32th Annual Meeting of the American Society for Bone Mineral and Research
  • Place of Presentation: Toronto, CANADA.
  • Year and Date: 20101015-20101019
• [Presentation] マウスSchcurri2欠失は腎25-hydroxyvitamin D 1-alpha hydroxylaseの発現高値と高カルシウム・リン積を呈して間接周囲の異所性石灰化をもたらす (2010)
  • Author(s): 長尾雅史、斎田良知、羽生亮、辺見弘明、納富拓也、早田匡芳, 中元哲也、金子和夫、黒澤尚、江面陽一、野田政樹
  • Organizer: 第25回日本整形外科学会
  • Place of Presentation: 京都
  • Year and Date: 20101014-20101015
• [Presentation] 副甲状腺ホルモンによる全身性骨量増加作用は交換神経系シグナルを必要とする (2010)
  • Author(s): 羽生亮、斎田良知、長尾雅史、辺見弘明、納富拓也、早田匡芳, 中元哲也、江面陽一、竹田秀、金子和夫、黒澤尚、野田政樹
  • Organizer: 第25回日本整形外科学会
  • Place of Presentation: 京都
  • Year and Date: 20101014-20101015
• [Presentation] Dullardは、骨芽細胞においてSmad1を標的としてBMP応答性の転写を抑制する (2010)
  • Author(s): 早田匡芳、江面陽一、野田政樹
  • Organizer: 新規BMP阻害因子第28回日本骨代謝学会
  • Place of Presentation: 東京
  • Year and Date: 20100721-20100723
• [Presentation] IL-1βはマウス軟骨細胞においてCIZの発現を促進する (2010)
  • Author(s): 元吉貴之、中元哲也、江面陽一、早田匡芳、納富拓也、長尾雅史、羽生亮、佐久間朋美、野田政樹
  • Organizer: 第28回日本骨代謝学会
  • Place of Presentation: 東京
  • Year and Date: 20100721-20100723
• [Presentation] CizによるRANKLのプロモーター制御機構の解析 (2010)
  • Author(s): 羽田佑、中元哲也、佐久間朋美、長尾雅史、早田匡芳、江面陽一、北澤理子、北澤荘平、野田政樹
  • Organizer: 第28回日本骨代謝学会
  • Place of Presentation: 東京
  • Year and Date: 20100721-20100723
• [Presentation] 転写因子CIZの欠損は、関節炎進展を抑制する (2010)
  • Author(s): 中元哲也、羽田佑、元吉貴之、佐久間朋美、早田匡芳、江面陽一、野田政樹
  • Organizer: 第28回日本骨代謝学会
  • Place of Presentation: 東京
  • Year and Date: 20100721-20100723
• [Presentation] Schnurri-2欠損マウスでは卵巣摘出後も野生型の骨量を維持する (2009)
  • Author(s): 長尾雅史、斎田良知、羽生亮、辺見弘明、納富拓也、早田匡芳、江面陽一、黒澤尚、野田政樹
  • Organizer: 第31回日本整形外科学会基礎学術集会
  • Place of Presentation: 横浜
  • Year and Date: 20091105-20091106
• [Presentation] Dullard, a novel phosphatase, that dephosphorylates and degrades BMP receptors, suppresses signaling in osteoblasts. (2009)
  • Author(s): Hayata T, Ezura Y, Noda M.
  • Organizer: The 31th Annual Meeting of the American Society for Bone Mineral and Research
  • Place of Presentation: Denver, Colorado, USA.
  • Year and Date: 20090911-20090915
• [Presentation] Anabolic Action of PTH/PTHrP Receptor Signaling in Bone is Suppressed by a Nucleocytoplasmic Shuttling Protein CIZ. (2009)
  • Author(s): Nakamoto T, Noriaki Ono, Hanyu R, Sakuma T, Hayata T, Ezura Y, Ernestina Schipani, Henry Kronenberg, Noda M.
  • Organizer: The 31th Annual Meeting of the American Society for Bone Mineral and Research
  • Place of Presentation: Denver, Colorado, USA.(口頭発表)
  • Year and Date: 20090911-20090915
• [Presentation] Deficiency of CIz, Cas Ieteractive Zinc Finger Protein, Suppresses Tumor Invasion into Bone. (2009)
  • Author(s): Sakuma T, Nakamoto T, Miyai K, Hayata T, Amagasa T, Ezura Y, Noda M.
  • Organizer: The 31th Annual Meeting of the American Society for Bone Mineral and Research
  • Place of Presentation: Denver, Colorado, USA.
  • Year and Date: 20090911-20090915
• [Presentation] Nanogel Scaffold Delivery of Prostaglandin E2 Receptor (EP4) Specific Agonist in Combination with BMP Repairs Microstructure of Bone Produced in the Defect via Potentiation of Transcription Activity of Smad Response Element. (2009)
  • Author(s): Kamolratanakul P, Kawamata A, Yamamoto Y, Hayata T, Ezura Y, Akiyoshi K, Amagasa T, Noda M.
  • Organizer: The 31th Annual Meeting of the American Society for Bone Mineral and Research
  • Place of Presentation: Denver, Colorado, USA.
  • Year and Date: 20090911-20090915
• [Presentation] PTH Signaling and Osteopontin Deficiency Coordinately Enhance Progenitor Niche for the Cells to Support Tooth Development. (2009)
  • Author(s): Morishita M, Ono N, Hanyu R, Hayata T, Kamolratanakul P, Hemmi H, Nagao M, Ezura Y, Noda M.
  • Organizer: The 31th Annual Meeting of the American Society for Bone Mineral and Research
  • Place of Presentation: Denver, Colorado, USA.
  • Year and Date: 20090911-20090915
• [Presentation] Schnurri-2 (SHN-2) deficiency counteracts against bone loss induced by ovariectomy. (2009)
  • Author(s): Nagao M, Saita Y, Nakamoto T, Notomi T, Hanyu R. Hayata T, Ezura Y, Noda M.
  • Organizer: The 31th Annual Meeting of the American Society for Bone Mineral and Research
  • Place of Presentation: Denver, Colorado, USA.
  • Year and Date: 20090911-20090915
• [Presentation] Sympathetic nervous tone modulates constitutively active parathyroid hormone receptor signaling in vivo. (2009)
  • Author(s): Hanyu R, Nagao M, Takeda S, Hemmi H, Notomi T, Hayata T, Ezura Y, Noda M.
  • Organizer: The 31th Annual Meeting of the American Society for Bone Mineral and Research
  • Place of Presentation: Denver, Colorado, USA.
  • Year and Date: 20090911-20090915
• [Presentation] BMP受容体を脱リン酸化し分解する新規脱リン酸化酵素Dullardは、骨芽細胞においてBMPシグナルを抑制する (2009)
  • Author(s): 早田匡芳、江面陽一、野田政樹
  • Organizer: 第27回日本骨代謝学会
  • Place of Presentation: 大阪
  • Year and Date: 20090723-20090725
• [Book] Mechanosensing Biology(Chapter 6. Mechanical Stress and Bone, in Part II Tissue and Gravity.)(Editor : Masaki Noda)ISBN : 978-4-431-89756-9. (2011)
  • Author(s): Noda M, Hayata T, Nakamoto T, Notomi T, Ezura Y
  • Total Pages: 71-86
  • Publisher: Springer