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2000 Fiscal Year Annual Research Report

骨粗鬆症の病態成立に関する分子生物学的機構の解明

Research Project

Project/Area Number 09307034
Research InstitutionTokyo Medical Dental University

Principal Investigator

野田 政樹  東京医科歯科大学, 難治疾患研究所, 教授 (50231725)

Co-Investigator(Kenkyū-buntansha) 山下 照仁  東京医科歯科大学, 難治疾患研究所, 助手 (90302893)
二藤 彰  東京医科歯科大学, 難治疾患研究所, 助教授 (00240747)
Keywords骨粗鬆症 / 破骨細胞 / 骨芽細胞 / 遺伝子制御 / オステオポンチン / klotho / Tob / メカニカルストレス
Research Abstract

本基盤研究においては、骨粗鬆症の病態生理学の基礎となる骨芽細胞・破骨細胞の研究を展開した.その結果、本研究による現在までの骨吸収に関する研究領域の成果としては,カルシウム向性制御因子である副甲状腺ホルモン、ビタミンDやTGFβを含むホルモンおよびサイトカインによって制御されるオステオポンチンのノックアウトマウスを作成し(Journal of Bone and Mineral Research,1998)、このマウスにおいおいては、閉経後骨粗鬆症モデルを作成すると、骨吸収が明らかに抑制されることから、オステオポンチンが骨粗鬆症の成立の上で重要な促進的役割を持つ分子であることを発見した(Proceedings of the National Academy of Sciences U.S.A.,1999).
更に、骨形成領域の研究の成果としては,骨芽細胞機能の制御の分子機構を解析し、新しいBMP制御分子TOBが、特異的に成体の動物の加齢後期において骨の形成の制御に関わることをin vivoで明らかにし(Cell,2000)、Smadの下流におけるCbfaの発現制御の機構(Journal of Biological Chemistry(JBC)1998)、ビタミンDによる抑制性の転写制御因子Idの発現阻害のメカニズム(JBC,1997a)、hellx-loop-helix型転写因子Scleraxisの機能の制御(JBC,1997b)、骨・軟骨系の分化に際してのHMG型の転写因子の制御メカニズム(JBC,2000)を発見した。
骨粗鬆症において重要な上記のような骨吸収および骨形成に関わる破骨細胞ならびに骨芽細胞の機能の平衡維持のメカニズムの研究領域の成果のとしては、老化に関わる制御分子、Klothoの機能(Endocrinology,2000;Journal of Endocrinology,2000)、ウィルスの発現系によるKlothoの遺伝子の制御機構(Jorunal of Gene Medicine,2000)を解明した。
さらに本研究の成果として、この重力などのメカニカルストレスがオステオポンチンとKlotho遺伝子がを介する制御(Journal of Experimental Medicine,2001)(Journalof Endocrinology,2001を明らかにした。
本基盤研究A(2)の遂行により、骨粗鬆症においてて骨形成・吸収・平衡バランスと老化の3つの主要な局面において中枢的な役割を持つ遺伝子を現在までの研究で解明し、個々の遺伝子の機能の解析に成果を上げた(英文原著39件,国際学会発表57件,受賞13件)。

  • Research Products

    (40 results)

All Other

All Publications (40 results)

  • [Publications] Ishijima,M.,Rittling,S.R.,Yamashita,T.,Tsuji,K.,Kurosawa,H.,Nifuji,A.,Denhardt,D.T., and Noda,M.: "Enhancement of osteoclastic bone resorption and suppression of osteoblastic bone formation in response to reduced mechanical stress do not occur in the absence of osteopontin."Journal of Experimental Medicine. 193. 399-404 (2001)

  • [Publications] Ihara,H.,Denhardt,D.T.,Furuya,K.,Yamashita,T.,Muguruma,y.,Tsuji,K.,Hruska,K.A.,Higashio,K.,Enomoto,S.,Nifuji,A.,Rittling,S.R.,and Noda,M.: "Parathyroid hormone-induced bone resorption does not occur in the absence of osteopontin."Journal of Biological Chemistry. 276(In Press). (2001)

  • [Publications] Asou Y.,Rittling S.R.,Yoshitake H.,Tsuji K.,Shinomiya K.,Nifji,A.,Denhardt D.T., and Noda M.: "Osteopontin facilitates angiogenesis, accumulation of osteoclasts and resorption in ectopic bone."Endocrinology. 142. 1325-1332 (2001)

  • [Publications] Nemoto H.,Rittling S.R.,Yoshitake H.,Furuya K.,Amegasa T.,Tsuji K.,Nifuji A.,Denhardt D.T. and Noda M.: "Osteopontin deficiency reduces experimental tumor cell metastasis to bone and soft tissues."Journal of Bone and Mineral Research. (In Press). (2001)

  • [Publications] Sekiya,I.,koopman,P.,Tsuji,K.,Mertin,S.,Harley,V.,Yamada,Y.,Shinomiya,K.,Nifuji,A., and Noda,M.: "Dexamethasone Enhances SOX9 Expression in Chondrocytes."Journal of Endocrinology. (In Press). (2001)

  • [Publications] Tsuji,K.,Kraut,N.,Groudine,M., and Noda,M.: "Vitamin D3 Enhances the Expression of I-mfa, an Inhibitor of MyoD Family, in Osteoblasts."Biochimica et Biophysica Acta. (In Press). (2001)

  • [Publications] Tsuji,K.and Noda,M.: "Transient Suppression of Cbfa 1 Expression by Basic Fibroblast Growth Factor (bFGF) in Rat Osteoblast-like Osteosarcoma ROS17/2.8 Cells."Journal of Bone and Mineral Metabolism. (In Press). (2001)

  • [Publications] Sekiya,I.,Koopman,P.,Tsuji,K.,Mertin,S.,Harley,V.,Yamada,Y.,Shinomiya,K.,Nifuji,A., and Noda,M.: "Transcriprional suppression of SOX9 expression by retinoic acid in chondrocytes. "Journal of Cellular Biochemistry. (In Press). (2001)

  • [Publications] Kawaguchi N.,Ono T.,Mochii M.and Noda M.: "Spontaneous mutation in Mitf gene causes osteopetrosis in silver homozygote quail."Developmental Dynamics. 220. 133-140 (2001)

  • [Publications] Yamashita T.,Sekiya I.,Kawaguchi N.,Kashimeda,K.,Nifuji,A.,Nabeshma Y.and Noda M.: "Klotho-deficient mice are resistant to bone loss induced by unloading due to sciatic neurectomy."Journal of Endocrinology. 168. 347-351 (2001)

  • [Publications] Yosida Y.,Tanaka S.,Umemori H.,Minowa O.,Usui M.,Ikematsu N.,Hosoda E.,Imamura T.,Kuno J.,Yamashita T.,Miyazono K.,Noda M.,Noda T.,and Yamamoto T.: "Negative regulation of BMP/Smad signaling by Tob in osteobiasts."Cell. 103. 1085-1097 (2000)

  • [Publications] Shiraid-lida T,lida A,Nabeshima Y,Anezawa H,Nishikawa S,Noda M, Kuro-o M,Nabeshima Y.: "Improvement of multiple pathophysiological phenotypes of klotho (kl/kl) mice by adenovirus-mediated expression of the klotho gene."J Gene Med. 2. 233-42 (2000)

  • [Publications] Furuya K.,Nakamoto T.,Shen Z.J.,Tsuji K.,Nifuji A.,Hirai H.and Noda M.: "Overexpression of Cas-interactiong zinc finger protein (CIZ) suppresses proliferation and enhances expression of type I collagen gene in osteoblast-like MC3T3E1 cells."Experimental Cell Research. 261. 329-335 (2000)

  • [Publications] Kawaguchi N.and Noda M.: "Mitf is expressed in osteoclast progenitors in vitro."Experimental Cell Research. 260. 284-291 (2000)

  • [Publications] Tsuji K.and Noda M.: "Identification and Expression of a novel 3'-exon of mouse Runx1/Pebp2αB/Cbfa2/AML1 gene."Biochemical and Biophysical Research Communications. 274. 171-176 (2000)

  • [Publications] Sekiya I.,Tsuji K.,Koopman P.,Watanabe H.,Yamada Y.,Shinomiya K.,Nifuji A., and Noda M.: "SOX9 enhances aggrecan gene promoter/enhancer activity and is upregulated by Retinoic Acid in a Cartilage-Derived Cell Line, TC6."Journal of Biological Chemistry. 275. 10738-10744 (2000)

  • [Publications] Takazawa Y.,Tsuji K.,Nifuji A.,Kurosawa H.,Ito Y,and Noda M.: "CBFA1, IS Constitutively expressed in chondrocytic cell line, TC6, and its expression is upregulated byBMP2."Journal of Endocrinology. 165. 579-586 (2000)

  • [Publications] Murakami S.and Noda M.: "Indian hedgehog during fracture healing in adult rat femora"Calcified Tissue International. 66. 272-276 (2000)

  • [Publications] Yamashita Y.,Yoshitake H.,Tsuji K.,Kawaguchi N.,Nabeshima Y., and Noda M.,: "Retardation in bone resorption after bone marrow ablation in klotho mutant mice."Endocrinology. 141. 438-445 (2000)

  • [Publications] Yamashita T.,Nabeshima Y.and Noda M.: "High-resolution uCT (micro-computed tomography) analyses of the abnormal trabecular bone structures in klotho gene mutant mice."Journal of Endocrinology. 164. 239-245 (2000)

  • [Publications] Hijikata M,Matsumoto HN,Kobayashi A,Nifuji A,Noda M,Natori S.: "Induction of apoptosis of monocyte-macrophage lineage cells by 5-S-GAD."FEBS Lett.. 457. 405-408 (1999)

  • [Publications] Nifuji A., and Noda M.: "Coordinated expression of noggin and BMPs during early skeletogenesis and induction of noggin expression by BMP7. "Journal of Bone and Mineral Research. 14. 2057-66 (1999)

  • [Publications] Yoshitake Y.,Ritting S.R.,Denhardt D.T.and Noda M.: "Osteopontin-deficient mice are resistant to ovariectomy-induced bone resorption."Proceedings of the National Academy of Sciences. 96. 8156-8160 (1999)

  • [Publications] Takazawa Y.,Nifuji A.,Mataga N.,Yamauchi Y.,Kurosawa H., and Noda M.: "Articular cartilage immortalized by a temperature sensitive mutant of SV40 large T antigen survive and form cartilage tissue in articular cartilage environment."Journal of Cellular Biochemistry. 74. 338-345 (1999)

  • [Publications] Nifuji A.,Odile Kellermann, and Noda M.: "Noggin expression in a mesodermal pluripotent cell line C1 and its regulation by BMP."Journal of Cellular Biochemistry. 73. 437-444 (1999)

  • [Publications] Furuya K.,Nifuji A.,Rosen V., and Noda M.: "Effects of GDF7/BMP12 on proliferation and alkaline phosphatase expression in rat osteoblastic osteosarcoma ROS 17/2.8 cells."Journal of Cellular Biochemistry. 72. 177-180 (1999)

  • [Publications] Tamura M.and Noda M.: "Identification of DERMO-1 as a member of helix-loop-helix type transcription factors expressed in osteoblastic cells."Journal of Cellular Biochemistry. 72. 167-176 (1999)

  • [Publications] Li J.,Tsuji K.,Komori T.,Miyazono K.,Nifuji A.,Wrana J.L., Ito Y. and Noda M.: "Smad2 overexpression enhances Smad4 gene expression and suppresses CBFA1 gene expression in osteoblastic osteosarcoma ROS17/2.8 cells and primary rat calvaria cells."Journal of Biological Chemistry. 273. 31009-31015 (1998)

  • [Publications] Kawaguchi N.and Noda M.: "Osteoblastic cells regulate mi gene expression in cultured bone marrow cells."International Journal of Hematology. 67. 275-281 (1998)

  • [Publications] Kawauchi T.,Nifuji A.,Mataga N.,Olson E.N.,Bonaventure J.,Shinomiya K.,Liu Y.and Noda M.: "Fibriblast growth factor down-regulates expression of a basic helix-loop-helix type transcription factor, scleraxis, in chondrocyte-like cells, TC6."Journal of Cellular Biochemistry. 70. 468-477 (1998)

  • [Publications] Ritting S.,Matsumoto H.N.,MoKee M.,Novik K,An X.R.,Nanci A.,Denhardt D.and Noda M.: "Mice lacking osteopontin show normal development and bone structure but display altered osteoclast formation in vitro"Journal of Bone and Mineral Research. 13. 1101-1111 (1998)

  • [Publications] Yamashita T.,Nifuji A.,Furuya K.,Nabeshima Y.and Noda M: "Elongation of the epiphseal trabecular bone associated with precocious aging in transgenic mice carrying an insertional mutaiton in klotho gene locus"J.Endocrinology. 159. 1-8 (1998)

  • [Publications] Tsuji K.,Ito Y.and Noda M.: "Expression of the PEBP2aA/AML3/CBFA1 gene is regulated by BMP4/7 heterodmer and its over expression suppresses type I collegene and osteocalcin gene expression in osteoblastic and nonosteoblastic mesenchymal cells."Bone. 22. 87-92 (1998)

  • [Publications] Ezura Y.,Tournay O.,Nifuji A.and Noda M.: "Identification of a novel suppressive vitamin D response sequence in the 5' flanking region of murine Id 1 gene."Journal of Biological Chemistry. 272. 29865-29872 (1997)

  • [Publications] Liu Y.,Watanabe H.,Yamada,Y.,Olson E.,Nifuji A.and Noda M.: "Overexpression of a single helix-loop-helix type transcription factor, scleraxis, enhances aggrecan gene expression in osteoblastic osteosarcoma ROS17/2.8 cells."Journal of Biological Chemistry. 272. 29880-29885 (1997)

  • [Publications] Liu Y.,Wozney J.,Nifuji A.,Olson E.and Noda M.: "Scleraxis is expressed in GC_<12> myoblasts and its level is down-regulated by bone morphogenetic protein-2 (BMP_2)。 Fibriblast growth lactor down-regulated expression of a basic helix-loop-helix type transcription factor.scleraxis in chondrocyte-like cells, TCa."Journal of Cellular Biochemistry. 67. 66-74 (1997)

  • [Publications] Matsue M.,Kageyama R.,Denhardt D.T.and Noda M.: "Helix-loop-helix type transcription tactor, HES-1, is expressed in osteoblastic cells, suppressed by 1,25(OH)2 vitarnin D3 and modulates 1,25(OH)2 vitarmin D3 enhancement of osteopontin expression."Bone. 20. 329-334 (1997)

  • [Publications] Murakami S.,Nifuji A.and Noda M.: "Expression of indian hedgehog in osteoblasts and its posttranscriptional regulation by transforming growth factor-b."Endocrinology. 138. 1972-1978 (1997)

  • [Publications] Nifuji A.,Kellerman O.,Kuboki Y.,Wozney J.and Noda M.: "Perturbation of BMP signaling in somitogenesis resulted in vertebral and rib malformation in the axial skeletal formation."Journal of Bone and Mineral Research. 12. 332-342 (1997)

  • [Publications] Noda M,Nifuji A.,Tsuji K,Furuya K,Sakiya I,Asou Y,Kawaguchi N and Yamashita T: "Frontiers in Bioscience"Transcription Factors and Osteoblasts. D817-820 (1998)

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Published: 2002-04-03   Modified: 2016-04-21  

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