Analysis of the functions of TACE in bone metabolism and hematopoiesis

• Project/Area Number: 21390424
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Keio University
• Principal Investigator: HORIUCHI Keisuke 慶應義塾大学, 医学部, 特任准教授 (30327564)
• Co-Investigator(Kenkyū-buntansha): TOYAMA Yoshiaki 慶應義塾大学, 医学部, 教授 (40129549)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥13,000,000 (Direct Cost: ¥10,000,000、Indirect Cost: ¥3,000,000); Fiscal Year 2011: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2010: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2009: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
• Keywords: 骨 / 軟骨代謝学 / TACE/ADAM10 / 骨代謝 / 血液幹細胞 / TACE

Research Abstract

In the present study we analyzed the functions of amembrane-bound metalloprotease, TACE, and found that it has a critical roles in theregulation of bone metabolism as well as hematopoiesis. In addition, we also generatedAdam10 mutant mice and revealed tha

Research Products

• [Journal Article] Brief report: requirement ofTACE/ADAM17 for hair follicle bulgeniche establishment. (2012)
  • Author(s): Nagao, K., T. Kobayashi, M. Ohyama, H.Akiyama, K. Horiuchi, and M. Amagai
  • Journal Title: Stem Cells Volume: 30 Pages: 1781-1785
  • Peer Reviewed
• [Journal Article] Stress-induced production ofchemokines by hair follicles regulates thetrafficking of dendritic cells in skin (2012)
  • Author(s): Nagao, K., T. Kobayashi, K. Moro, M.Ohyama, T. Adachi, D. Y. Kitashima, S.Ueha, K. Horiuchi, H. Tanizaki, K.Kabashima, A. Kubo, Y. H. Cho, B. E.Clausen, K. Matsushima, M. Suematsu,G. C. Furtado, S. A. Lira, J. M. Farber,M. C. Udey, and M. Amagai.
  • Journal Title: NatImmunol Volume: 13 Pages: 744-752
  • Peer Reviewed
• [Journal Article] EpidermalADAM17 maintains the skin barrier byregulating EGFR ligand-dependentterminal keratinocyte differentiation (2012)
  • Author(s): Franzke, C. W., C. Cobzaru, A.Triantafyllopoulou, S. Loffek, K.Horiuchi, D. W. Threadgill, T. Kurz, N.van Rooijen, L. Bruckner-Tuderman,and C. P. Blobel.
  • Journal Title: JExp Med Volume: 209 Pages: 1105-1119
  • Peer Reviewed
• [Journal Article] Lungendothelial ADAM17 regulates the acuteinflammatory response tolipopolysaccharide. (2012)
  • Author(s): Dreymueller, D., C. Martin, T. Kogel, J.Pruessmeyer, F. M. Hess, K. Horiuchi, S.Uhlig, and A. Ludwig.
  • Journal Title: EMBO Mol Med Volume: 4 Pages: 412-423
  • Peer Reviewed
• [Journal Article] TACE (ADAM17)inhibits Schwann cell myelination (2012)
  • Author(s): La Marca, R., F. Cerri, K. Horiuchi, A.Bachi, M. L. Feltri, L. Wrabetz, C. P.Blobel, A. Quattrini, J. L. Salzer, and C.Taveggia.
  • Journal Title: NatNeurosci Volume: 14 Pages: 857-865
  • Peer Reviewed
• [Journal Article] Dual functions ofcell-autonomous and non-cell-autonomous ADAM10 activityin granulopoiesis (2011)
  • Author(s): Yoda, M., T. Kimura, T. Tohmonda, S.Uchikawa, T. Koba, J. Takito, H.Morioka, M. Matsumoto, D. C. Link, K.Chiba, Y. Okada, Y. Toyama, and K.Horiuchi.
  • Journal Title: Blood Volume: 118 Pages: 6939-6942
  • Peer Reviewed
• [Journal Article] The IRE1alpha-XBP1pathway is essential for osteoblastdifferentiation through promotingtranscription of Osterix. (2011)
  • Author(s): Tohmonda, T., Y. Miyauchi, R. Ghosh,M. Yoda, S. Uchikawa, J. Takito, H.Morioka, M. Nakamura, T. Iwawaki, K.Chiba, Y. Toyama, F. Urano, and K.Horiuchi.
  • Journal Title: EMBO Rep Volume: 12 Pages: 451-457
  • Peer Reviewed
• [Journal Article] Activation ofTNFR1 ectodomain shedding bymitochondrial Ca2+ determines theseverity of inflammation in mouse lungmicrovessels. (2011)
  • Author(s): Rowlands, D. J., M. N. Islam, S. R. Das,A. Huertas, S. K. Quadri, K. Horiuchi, N.Inamdar, M. T. Emin, J. Lindert, V. S.Ten, S. Bhattacharya, and J.Bhattacharya
  • Journal Title: J Clin Invest Volume: 121 Pages: 1986-1999
  • Peer Reviewed
• [Journal Article] Tumor Necrosis Factor-alphaConverting Enzyme InactivationAmeliorates High-Fat Diet-InducedInsulin Resistance and Altered EnergyHomeostasis (2011)
  • Author(s): Kaneko, H., T. Anzai, K. Horiuchi, K.Morimoto, A. Anzai, T. Nagai, Y. Sugano,Y. Maekawa, H. Itoh, T. Yoshikawa, Y.Okada, S. Ogawa, and K. Fukuda
  • Journal Title: Circ J Volume: 75 Pages: 2482-2490
  • Peer Reviewed
• [Journal Article] Tumornecrosis factor-alpha converting enzymeis a key mediator of abdominal aorticaneurysm development. (2011)
  • Author(s): Kaneko, H., T. Anzai, K. Horiuchi, T.Kohno, T. Nagai, A. Anzai, T. Takahashi,A. Sasaki, M. Shimoda, Y. Maekawa, H.Shimizu, T. Yoshikawa, Y. Okada, R.Yozu, and K. Fukuda.
  • Journal Title: Atherosclerosis Volume: 218 Pages: 470-478
  • Peer Reviewed
• [Journal Article] Gene expression profilingof mouse growth plate cartilage by lasermicrodissection and microarray analysis. (2011)
  • Author(s): Isshiki, H., K. Sato, K. Horiuchi, S.Tsutsumi, M. Kano, H. Ikegami, H. Abe,A. Umezawa, H. Aburatani, and Y.Toyama.
  • Journal Title: J Orthop Sci Volume: 16 Pages: 670-672
  • Peer Reviewed
• [Journal Article] Leukocyte ADAM17 RegulatesAcute Pulmonary Inflammation. (2011)
  • Author(s): Arndt, P. G., B. Strahan, Y. Wang, C.Long, K. Horiuchi, and B. Walcheck
  • Journal Title: PLoSOne Volume: 6
  • Peer Reviewed
• [Journal Article] Dual functions of cell-autonomous and non-cell-autonomous ADAM10 activity in granulopoiesis (2011)
  • Author(s): Yoda, M., et al
  • Journal Title: Blood Volume: 118 Pages: 6939-6942
  • Peer Reviewed
• [Journal Article] The IRE1alpha-XBP1 pathway is essential for osteoblast differentiation through promoting transcription of Osterix. (2011)
  • Author(s): Tohmonda, T, et al.
  • Journal Title: EMBO Reports Volume: (In press)
  • Peer Reviewed
• [Journal Article] Ectodomain shedding ofEGFR ligands and TNFR1 dictateshepatocyte apoptosis during fulminanthepatitis in mice. (2010)
  • Author(s): Murthy, A., V. Defamie, D. S. Smookler,M. A. Di Grappa, K. Horiuchi, M.Federici, M. Sibilia, C. P. Blobel, and R.Khokha.
  • Journal Title: J Clin Invest Volume: 120 Pages: 2731-2744
  • Peer Reviewed
• [Journal Article] Invivo role of leukocyte ADAM17 in theinflammatory and host responses duringE. coli-mediated peritonitis. (2010)
  • Author(s): Long, C., Y. Wang, A. H. Herrera, K.Horiuchi, and B. Walcheck.
  • Journal Title: J LeukocBiol Volume: 87 Pages: 1097-1101
  • Peer Reviewed
• [Journal Article] Receptor Activator of NF-{kappa}B(RANK) Ligand Induces EctodomainShedding of RANK in Murine RAW264.7Macrophages. (2010)
  • Author(s): Hakozaki, A., M. Yoda, T. Tohmonda, M.Furukawa, T. Hikata, S. Uchikawa, H.Takaishi, M. Matsumoto, K. Chiba, K.Horiuchi, and Y. Toyama
  • Journal Title: J Immunol Volume: 184 Pages: 2442-2448
  • Peer Reviewed
• [Journal Article] ADAM17 deletion in thymic epithelialcells alters aire expression withoutaffecting T cell developmentalprogression. (2010)
  • Author(s): Gravano, D. M., B. T. McLelland, K.Horiuchi, and J. O. Manilay.
  • Journal Title: PLoS One Volume: 5
  • Peer Reviewed
• [Journal Article] Receptor Activator of NF-_KB Ligand Induces Ectodomain Shedding of Receptor Activator of NF-_KB in Murine RAW264.7 Macrophages (2010)
  • Author(s): Hakozaki, A., et al.
  • Journal Title: The Journal of Immunology 184 Pages: 2442-2448
  • Peer Reviewed
• [Journal Article] ADAMs 10 and 17represent differentially regulatedcomponents of a general sheddingmachinery for membrane proteins suchas transforming growth factor alpha,L-selectin, and tumor necrosis factoralpha (2009)
  • Author(s): Le Gall, S. M., P. Bobe, K. Reiss, K.Horiuchi, X. D. Niu, D. Lundell, D. R.Gibb, D. Conrad, P. Saftig, and C. P.Blobel.
  • Journal Title: Mol Biol Cell Volume: 20 Pages: 1785-1794
  • Peer Reviewed
• [Journal Article] Ectodomain shedding ofFLT3 ligand is mediated by TNF-alphaconverting enzyme. (2009)
  • Author(s): Horiuchi, K., H. Morioka, H. Takaishi,H. Akiyama, C. P. Blobel, and Y.Toyama
  • Journal Title: J Immunol Volume: 182 Pages: 7408-7414
  • Peer Reviewed
• [Journal Article] Conditional inactivation of TACE by aSox9 promoter leads to osteoporosis andincreased granulopoiesis viadysregulation of IL-17 and G-CSF (2009)
  • Author(s): Horiuchi, K., T. Kimura, T. Miyamoto, K.Miyamoto, H. Akiyama, H. Takaishi, H.Morioka, T. Nakamura, Y. Okada, C. P.Blobel, and Y. Toyama.
  • Journal Title: J Immunol Volume: 182 Pages: 2093-2101
  • Peer Reviewed
• [Journal Article] Ectodomain shedding of FLT3 ligand is mediated by TNF-alpha converting enzyme (2009)
  • Author(s): Horiuchi, K., et al.
  • Journal Title: The Journal of Immunology 182 Pages: 7408-7414
  • Peer Reviewed
• [Journal Article] Emerging roles of TACE as a central component of ectodomain shedding in vivo (2009)
  • Author(s): Horiuchi, K
  • Journal Title: 核酸・酵素・蛋白 54 Pages: 1728-1734
  • NAID: 40016835261
• [Presentation] 軟骨細胞特異的にTACEを不活化したマウスは成長板の肥厚と長管骨の成長障害を生じる (2012)
  • Author(s): 堀内圭輔
  • Organizer: 第25回日本軟骨代謝学会
  • Place of Presentation: ウィルあいち(名古屋)
  • Year and Date: 2012-03-09
• [Presentation] 小胞体ストレス応答経路であるIRE1α-XBP1はBMPによる骨芽細胞分化に必須である (2011)
  • Author(s): 堀内圭輔
  • Organizer: 第26回日本整形外科学会基礎学術集会
  • Place of Presentation: 群馬県民会館(前橋)
  • Year and Date: 2011-11-21
• [Presentation] IL-1受容体シグナルにおけるTNFα converting enzyme (TACE)の機能解析 (2011)
  • Author(s): 内川伸一
  • Organizer: 第26回日本整形外科学会基礎学術集会
  • Place of Presentation: 群馬県民会館(前橋)
  • Year and Date: 2011-11-21
• [Presentation] Regulation of myelination bysecretase: role of Adam17/TACE (2011)
  • Author(s): La Marca, R., F. Cerri, K. Horiuchi,A. Bachi, M. Laura Fltri, L. Wrabetz,C. P. Blobel, J. L. Salzer, and C.Taveggia
  • Organizer: Society of Neuroscience meeting
  • Place of Presentation: Washington USA
  • Year and Date: 2011-11-13
• [Presentation] IL-1受容体シグナルにおけるTNFα converting enzyme (TACE) の機能解析 (2011)
  • Author(s): 内川伸一, 依田昌樹, 千葉一裕, 堀内圭輔, and 戸山芳昭
  • Organizer: 第26回日本整形外科学会基礎学術集会
  • Place of Presentation: 前橋
  • Year and Date: 2011-10-27
• [Presentation] 小胞体ストレス応答経路であるIRE1α-XBP1はBMPによる骨芽細胞分化に必須である (2011)
  • Author(s): 堀内圭輔, 東門田誠一, 森岡秀夫,戸山芳昭, and 千葉一裕
  • Organizer: 第26回日本整形外科学会基礎学術集会
  • Place of Presentation: 前橋
  • Year and Date: 2011-10-27
• [Presentation] 小胞体ストレス応答機構Xbp1α-XBP1経路は,骨芽細胞分化過程において活性化されOsterixの転写を促進する (2011)
  • Author(s): 東門田誠一, 戸山芳昭, and 堀内圭輔
  • Organizer: 第12回運動器学研究会
  • Place of Presentation: 高知
  • Year and Date: 2011-09-03
• [Presentation] 小胞体ストレス応答機構Xbp1α-XBP1経路は,骨芽細胞分化過程において活性化されOsterixの転写を促進する (2011)
  • Author(s): 東門田誠一
  • Organizer: 第12回運動器学研究会
  • Place of Presentation: 土佐ロイヤルホテル(高知)
  • Year and Date: 2011-09-02
• [Presentation] 小胞体ストレス応答機構Xbp1α-XBP1経路は,骨芽細胞分化過程において活性化されOsterixの転写を促進する (2011)
  • Author(s): 東門田誠一
  • Organizer: 第29回日本骨代謝学会学術集会
  • Place of Presentation: 大阪国際会議場(大阪)
  • Year and Date: 2011-07-28
• [Presentation] IL-1受容体シグナリングにおけるTNF-α converting enzyme (TACE)の機能解析 (2011)
  • Author(s): 内川伸一
  • Organizer: 第29回日本骨代謝学会学術集会
  • Place of Presentation: 大阪国際会議場(大阪)
  • Year and Date: 2011-07-28
• [Presentation] IL-1受容体シグナリングにおけるTNF-α converting enzyme (TACE) の機能解析 (2011)
  • Author(s): 内川伸一, 依田昌樹, 千葉一裕, 堀内圭輔, and 戸山芳昭
  • Organizer: 第29回日本骨代謝学会学術集会
  • Place of Presentation: 神戸
  • Year and Date: 2011-07-20
• [Presentation] 小胞体ストレス応答機構Xbp1α-XBP1経路は,骨芽細胞分化過程において活性化されOsterixの転写を促進する (2011)
  • Author(s): 東門田誠一, 宮内芳輝, 千葉一裕,戸山芳昭, and 堀内圭輔
  • Organizer: 第29回日本骨代謝学会学術集会
  • Place of Presentation: 神戸
  • Year and Date: 2011-07-20
• [Presentation] Conditionalinactivation of TACE inchondroblasts results in shorterlong bones and defective fracturehealing. (2011)
  • Author(s): Horiuchi, K., K. Saito, T. Kimura, K. Sato, Y. Okada, and Y. Toyama
  • Organizer: Gordon ResearchConference (Regulated Proteolysisof Cell Surface Proteins)
  • Place of Presentation: Davidson,NC USA
  • Year and Date: 2011-07-14
• [Presentation] Conditional inactivation of TACE in chondroblasts results in shorter long bones and defective fracture healing (2011)
  • Author(s): Keisuke Horiuchi
  • Organizer: Gordon Research Conference (Regulated Proteolysis of Cell Surface Proteins)
  • Place of Presentation: Davidson, NC, USA
  • Year and Date: 2011-07-12
• [Presentation] 2型コラーゲンプロモーターによりTACEを不活化したマウスは骨の成長障害を来たす (2011)
  • Author(s): 堀内圭輔, 斉藤憲太, 木村徳宏, 佐藤和毅, 秋山治彦, 岡田保典, 千葉一裕, and 戸山芳昭
  • Organizer: 第43回日本結合組織学会学術集会,第58回マトリックス研究会大会 合同学術集会
  • Place of Presentation: 別府
  • Year and Date: 2011-06-11
• [Presentation] 2型コラーゲンプロモーターによりTACEを不活化したマウスは骨の成長障害を来たす (2011)
  • Author(s): 堀内圭輔
  • Organizer: 43回日本結合組織学会学術集会,第58回マトリックス研究会大会合同学術集会
  • Place of Presentation: 大分ビーコンプラザ(大分)
  • Year and Date: 2011-06-11
• [Presentation] Studies from TACE Mutant Mice (2010)
  • Author(s): Horiuchi, K
  • Organizer: Biochemistry and Molecular Biology 2010
  • Place of Presentation: Kobe
  • Year and Date: 2010-12-19
• [Presentation] Studiesfrom TACE mutant mice (2010)
  • Author(s): Horiuchi, K.
  • Organizer: The 33rdAnnual Meeting of the MolecularBiology Society of Japan
  • Place of Presentation: Kobe
  • Year and Date: 2010-12-09
• [Presentation] 軟骨細胞分化および骨折治療過程におけるTNF α converting enzyme (TACE)の機能解析 (2010)
  • Author(s): 斎藤憲太
  • Organizer: 25回日本整形外科学会基礎学術集会
  • Place of Presentation: 京都
  • Year and Date: 2010-11-14
• [Presentation] 軟骨細胞分化および骨折治療過程におけるTNFαconverting enzyme(TACE)の機能解析 (2010)
  • Author(s): 斎藤憲太, 堀内圭輔, 木村徳宏, 佐藤和毅, 千葉一裕, 秋山治彦, and 戸山芳昭
  • Organizer: 第25回日本整形外科学会基礎学術集会
  • Place of Presentation: 京都
  • Year and Date: 2010-10-15
• [Presentation] 2型コラーゲンプロモーターによりTACEを不活化したマウスは骨の成長障害を来たす (2010)
  • Author(s): 堀内圭輔, 斉藤憲太, 木村徳宏, 佐藤和毅, 秋山治彦, 岡田保典, 千葉一裕, and 戸山芳昭
  • Organizer: 第11回運動器学研究会
  • Place of Presentation: 軽井沢
  • Year and Date: 2010-08-26
• [Presentation] 2型コラーゲンプロモーターによりTACEを不活化したマウスは骨の成長障害を来たす (2010)
  • Author(s): 堀内圭輔, 斎藤憲太, 高石官成, 秋山治彦, 佐藤和毅, 中村孝志, 千葉一裕, and 戸山芳昭
  • Organizer: 第83回日本整形外科学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2010-05-28
• [Presentation] 軟骨細胞分化におよび骨折治癒過程におけるTNF α converting enzyme (TACE)の機能解析 (2010)
  • Author(s): 斎藤憲太
  • Organizer: 第23回日本軟骨代謝学会
  • Place of Presentation: 鹿児島
  • Year and Date: 2010-04-03
• [Presentation] 軟骨細胞分化におよび骨折治癒過程におけるTNFaconverting enzyme (TACE)の機能解析 (2010)
  • Author(s): 斎藤憲太, 堀内圭輔, 木村徳宏, 佐藤和毅, 千葉一裕, 秋山治彦, and 戸山芳昭.
  • Organizer: 第23回日本軟骨代謝学会
  • Place of Presentation: 鹿児島
  • Year and Date: 2010-04-02
• [Presentation] Inhibitory effect of HGF on BMP-2 induced osteoblast differentiationin vitro. (2010)
  • Author(s): Kawasaki, T., Y. Niki, T. Miyamoto,K. Horiuchi, M. Matsumoto, M. Aizawa,and Y. Toyama
  • Organizer: 56th Annual Meeting ofthe Orthopaedic Research Society
  • Place of Presentation: New Orleans, Louisiana USA
  • Year and Date: 2010-03-06
• [Presentation] TACEはFlt3リガンドを可溶化する主要な酵素である (2009)
  • Author(s): 堀内圭輔
  • Organizer: 第24回日本整形外科学会基礎学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2009-11-06
• [Presentation] Conditional inactivation of TACE bya Sox9 promoter leads toosteoporosis and increasedgranulopoiesis via dysregulation ofIL-17 and G-CSF. (2009)
  • Author(s): Horiuchi, K.
  • Organizer: MMP GordonResearch Conference.
  • Place of Presentation: les diablerets,Switzerland
  • Year and Date: 2009-09-02
• [Presentation] Conditional inactivation of TACE by a Sox9 promoter leads to osteoporo sis and increased granulopoiesis via dysregulation of IL-17 and G-CSF (2009)
  • Author(s): 堀内圭輔
  • Organizer: Gordon Research Conference(MMP)
  • Place of Presentation: Les Diablerets, Switzerland
  • Year and Date: 2009-09-02
• [Presentation] 2型コラーゲンプロモーターによりTACEを不活化したマウスは骨の成長障害を来たす (2009)
  • Author(s): 堀内圭輔, 高石官成, 秋山治彦, 中村考志, and 戸山芳昭
  • Organizer: 第27回日本骨代謝学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2009-07-24
• [Presentation] 2型コラーゲンプロモーターによりTACEを不活化したマウスは骨の成長障害を来たす (2009)
  • Author(s): 堀内圭輔
  • Organizer: 第27回日本骨代謝学会
  • Place of Presentation: 大阪
  • Year and Date: 2009-07-24
• [Presentation] Studiesfrom TACE muntant mice. (2009)
  • Author(s): 堀内圭輔
  • Organizer: JointConference of 8th Pan-PacificConnective Tissue SocietiesSymposium (PPCTSS), 41st AnnualMeeting of the Japanese Society ofConnective Tissue Research (JSCTR),and 56th Annual Meeting of the JapanMatrix Club (JMC)
  • Place of Presentation: 横須賀
  • Year and Date: 2009-06-05
• [Presentation] Studies from TACE muntant mice (2009)
  • Author(s): 堀内圭輔
  • Organizer: Joint Conference of 8th Pan-Pacific Connective Tissue Societies Symposium, 41st Annual Meeting of the Japanese Society of Connective Tissue Research, and 56th Annual Meeting of the Japan Matrix Club
  • Place of Presentation: 横須賀
  • Year and Date: 2009-06-05
• [Book] Emerging rolesof TACE as a central component ofectodomain shedding in vivo (2009)
  • Author(s): Horiuchi, K
  • Publisher: Tanpakushitsu Kakusan Koso
• [Remarks]
  • URL: http://www.keio-ortho.jp/orthopaedic/group05_03.html