間葉系組織構築を制御する増殖分化因子群

• Project/Area Number: 12215066
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyoto University
• Principal Investigator: 開 祐司 京都大学, 再生医科学研究所, 教授 (40144498)
• Co-Investigator(Kenkyū-buntansha): 宿南 知佐 京都大学, 再生医科学研究所, 助教授 (60303905)
• Project Period (FY): 2000 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥45,000,000 (Direct Cost: ¥45,000,000); Fiscal Year 2004: ¥9,000,000 (Direct Cost: ¥9,000,000); Fiscal Year 2003: ¥9,000,000 (Direct Cost: ¥9,000,000); Fiscal Year 2002: ¥9,000,000 (Direct Cost: ¥9,000,000); Fiscal Year 2001: ¥9,000,000 (Direct Cost: ¥9,000,000); Fiscal Year 2000: ¥9,000,000 (Direct Cost: ¥9,000,000)
• Keywords: 血管侵入障壁 / 組織間相互作用 / 腫瘍血管新生 / Chondromodulin-I / Tenomodulin / Multiple Endocrine Neoplasia type 2 / 抗リウマチ / 機能性細胞外マトリックス / 血管侵入障 / ChM-I / TeM / 腱・靭帯 / 脱落膜 / アデノウイルスベクター / 軟骨 / 血管新生抑制因子 / chondromodulin-I / tenomodulin / ノックアウトマウス / 強靭結合組織 / 眼組織 / 網膜内皮細胞 / ゼブラフィッシュ / 唾液腺多形腺種 / chondromodulin-1 / 軟骨肉腫 / 転写制御 / 軟骨分化

Research Abstract

我々は典型的な無血管組織である軟骨から組織特異的に発現する血管新生抑制因子を発見し、Chondromodulin-I(ChM-I)と命名した。ChM-Iは、膜型前駆体からプロセシングされる分泌性糖タンパク質(121アミノ酸残基)で、血管新生を抑制する。組換えヒトChM-Iの局所投与は、in vivo固形腫瘍モデルにおける腫瘍血管新生を抑制した。最近、ChM-1に相同性を有する新規遺伝子として、Tenomodulin(TeM)を同定した。TeMは、腱、靭帯などの血管に乏しい強靱結合組織に特異的に発現していた。そこで、成熟型ChM-IとヒトTeMのC末端領域を発現分泌するアデノウイルスベクターを構築し、血管新生抑制作用を確認するとともに、in vivoにおける抗腫瘍活性を明らかにした。また、今回、Multiple Endocrine Neoplasia type 2(MEN 2B) Medullary Thyroid Carcinoma (MTC)に特徴的な高発現する遺伝子の一つとしてChM-Iを同定することに成功した。甲状腺C細胞におけるChM-Iの発現亢進がMEN 2B患者にみられるMarfan症候群様の骨格異常に寄与している可能性が示された。既にChM-Iノックアウトマウスで骨リモデリングの低下が認められている事実とあわせて、今後、骨・軟骨代謝におけるChM-Iのin vivo作用の詳細な解明が注目される。一方、リウマチ関節炎は関節軟骨部における血管新生のみならず病的な免疫応答による軟骨破壊を伴う。そこで、マウスに作成したリウマチ関節炎モデルを用いて、組換えChM-Iの作用を検討した。その結果、血管新生の抑制に加えて、新たにChM-IがCD4T細胞に作用して抗原特異的免疫応答を抑制すること、また、滑膜細胞の増殖を抑制することが判明した。

Research Products

• [Journal Article] Chondromodulin-I, a cartilage-derived angiogenesis inhibitory factor, Suppresses T cell response ; an implication of a therapeutic potential for arthritis. (2004)
  • Author(s): K.Setoguchi
  • Journal Title: Arthritis Rheum. 50 Pages: 828-839
• [Journal Article] Anti-angiogenic action of the C-terminal domain of tenomodulin that shares homology with chondromodulin-I. (2004)
  • Author(s): Y.Oshima
  • Journal Title: J.Cell Sci. 117 Pages: 2731-2744
• [Journal Article] Molecular Basis for the Aggressive Tumor Phenotype and Skeletal Abnormalities in Multiple Endocrine Neoplasia type 2B Syndrome. (2004)
  • Author(s): S.Jain
  • Journal Title: Caner Res. 64 Pages: 3907-3913
• [Journal Article] Active proliferation of mesenchymal cells prior to the chondrogenic repair response in rabbit full-thickness defects of articular cartilage. (2004)
  • Author(s): H.Mizuta
  • Journal Title: Osteoarthritis Cartilage 12 Pages: 586-596
• [Journal Article] One day exposure to FGF-2 was sufficient for the regenerative repair of full-thickness defects of articular cartilage in rabbits. (2004)
  • Author(s): H.Chums
  • Journal Title: Osteoarthritis Cartilage 12 Pages: 834-842
• [Publications] Y.Oshima: "Expression and localization of tenomodulin, a transmembrane type chondromodulin-I related angiogenic inhibitor, in mouse eyes."Invest.Ophthalmol.Vis.Sci.. 44. 1814-1823 (2003)
• [Publications] T.Hayami: "Expression of the cartilage derived anti-angiogenic factor chondromodulin-I decreases in the early stage of experimental osteoarthritis."J.Rheumatol. 30. 2207-2217 (2003)
• [Publications] K.Kusafuka: "Immunohistochemical evaluation of cartilage-derived morphogenetic protein-1 and -2 in normal human salivary glands and pleomorphic adenomas."Virchows Arch.. 442. 482-490 (2003)
• [Publications] N.Watanabe: "Suppression of differentiation and proliferation of early chondrogenic cells by Notch."J.Bone Miner.Metab.. 21. 344-352 (2003)
• [Publications] Y.Oshima: "Anti-angiogenic action of the C-terminal domain of tenomodulin that shares homology with chondromodulin-I."J.Cell Sci.. (印刷中).
• [Publications] K.Kusafuka: "Cartilage-specific matrix protein, chondromodulin-1 (OhM-1), is a strong angio-inhibitor in endochondral ossification of human neonatal vertebral tissues in vivo : relationship with anaioaenic factors in the cartilage"Acta Histochem.. 104. 167-175 (2002)
• [Publications] H.Inoue: "Phenotypic switching of in vitro mandibular chondylar cartilage during matrix mineralization"Anat. Science Int.. 77. 237-246 (2002)
• [Publications] Y.Nakamichi: "Chondromodulin-1 (ChM-1) is a bone remodeling factor"Mol.Cell.Biol.. 23. 636-644 (2003)
• [Publications] Y.Oshima. (印刷中). (2003)
• [Publications] A.Shimizu: "A novel alternative spliced FGFR3 isoform expressed during chondrogenic differentiation of ATDC5 cells has different ligand specificity from complete FGFR3"J. Biol. Chem.. 276. 11031-11040 (2001)
• [Publications] H.Funaki: "Expression and localization of angiogenic inhibitory factor, chondromodulin-I, in adult rat eye"Invest. Ophthalmol. Vis. Sci.. 42. 1193-1200 (2001)
• [Publications] K.Kusafuka: "Cartilage-specific matrix protein chondromodulin-I (ChM-I) is associated with chondroid formation in salivary pleomorphic adenomas : an immunohistochemical analysis"Am. J. Pathol.. 158. 1465-1472 (2001)
• [Publications] S.W.Sachdev: "Sequence analysis of zebrafish chondromodulin-I and expression profile in the notochord and chondrogenic regions of developing cartilage"Mech. Dev.. 105. 157-162 (2001)
• [Publications] C.Shukunami: "Molecular cloning of tenomodulin, a novel chondromodulin-I related gene"Biochem. Biophys. Res. Commun.. 280. 1323-1327 (2001)
• [Publications] C.Shukunami: "Requirement of autocrine signaling by bone morphogenetic protein-4 for chondrogenic differentiation of ATDC5 cells"FEBS Lett.. 469. 83-87 (2000)
• [Publications] S.Kudo: "Inhibition of chondrogenesis by parathyroid hormone in vivo during repair of full-thickness defects of articular cartilage."J.Bone Miner.Res.. 15. 253-260 (2000)
• [Publications] J.Guicheux: "A novel in vitro culture systemn for analysis of function of phosphate transport in endochondral ossification."Bone. 27. 69-74 (2000)
• [Publications] Y.Hiraki: "Chondromodulin-1 as a novel cartilage-specific growth-modulating factor."Pediatric Nephrology. 14. 602-605 (2000)
• [Publications] I.Yanagihara: "Genomic organization of the human chondromodulin-1 gene contaiing a promoter region which confers the expression of reporter gene in condrogenic ATDC5 Cells."J.Bone Miner.Res.. 15. 421-429 (2000)
• [Publications] A.Shimizu: "A novel alternative spliced FGFR3 isoform expressed during chondrogenic differentiation of ATDC5 cells has different ligand specificity from complete FGFR3."J.Biol.Chem.. (in press). (2001)