変形性関節症の新規治療法開発を目指したＮｏｔｃｈシグナルの網羅的解析

• 研究課題/領域番号: 23390358
• 研究種目: 基盤研究(B)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 整形外科学
• 研究機関: 東京大学
• 研究代表者: 筑田 博隆 東京大学, 医学部附属病院, 講師 (30345219)
• 研究分担者: 川口 浩 東京大学, 医学部附属病院, 届出診療医 (40282660) ; 大橋 暁 東京大学, 医学部附属病院, 助教 (20466767) ; 唐司 寿一 東京大学, 医学部附属病院, 助教 (40597762)
• 研究期間 (年度): 2011-04-01 – 2014-03-31
• 研究課題ステータス: 完了 (2013年度)
• 配分額: 18,980千円 (直接経費: 14,600千円、間接経費: 4,380千円); 2013年度: 5,720千円 (直接経費: 4,400千円、間接経費: 1,320千円); 2012年度: 4,290千円 (直接経費: 3,300千円、間接経費: 990千円); 2011年度: 8,970千円 (直接経費: 6,900千円、間接経費: 2,070千円)
• キーワード: 関節軟骨 / 変形性関節症 / Notchシグナル

研究概要

Notchシグナルにおいては隣接する細胞表面に存在するリガンドが受容体(Notch1-4)に結合すると細胞内ドメイン(ICD)が核内移行して転写抑制因子Rbpjと結合し、転写促進複合体としてHes/Heyなどの標的転写因子を誘導する。Notch1,2はマウス・ヒト関節軟骨細胞に発現し、軟骨変性に伴ってICDが核内移行していたことから、タモキシフェン誘導性軟骨特異的Creマウスを用いて成長後にRbpjをノックアウトして変形性関節症（OA）モデルを作成したところ、OAの進行は抑制された。さらにHes1-floxマウスを用いて同様の解析を行ったところ、OAの進行は抑制された。

研究成果

• [雑誌論文] Morphological characteristics of cervical spine in patients with athetoid cerebral palsy and the accuracy of pedicle screw placement (2014)
  • 著者名/発表者名: Kato S, Shoda N, Chikuda H, Seichi A, Takeshita K
  • 雑誌名: Spine 巻: 39(8)
• [雑誌論文] Identification of fibroblast growth factor-18 as a molecule to protect adult articular cartilage by gene expression profiling (2014)
  • 著者名/発表者名: Mori Y, Saito T, Chang SH, Kobayashi H, Ladel CH, Guehring H, Chung UI, Kawaguchi H
  • 雑誌名: J Biol Chem 巻: 289 ページ: 10192-200
• [雑誌論文] Incidence and risk factors for mortality of vertebral osteomyelitis : a retrospective analysis using the Japanese diagnosis procedure combination database (2013)
  • 著者名/発表者名: Akiyama T, Chikuda H, Yasunaga H, Horiguchi H, Fushimi K, Saita K
  • 雑誌名: BMJ Open 巻: 3(3)
• [雑誌論文] Generation of Col2a1-EGFP-iPS cells for monitoring chondrogenic differentiation (2013)
  • 著者名/発表者名: Saito T, Yano F, Mori D, Ohba S, Hojo H, Otsu M, Eto K, Nakauchi H, Tanaka S, Chung UI, Kawaguchi H
  • 雑誌名: PLoS ONE 巻: 8
• [雑誌論文] Transcriptional induction of ADAMTS5 by an NF-κB family member RelA/p65 in chondrocytes during osteoarthritis development (2013)
  • 著者名/発表者名: Kobayashi H, Hirata M, Saito T, Itoh S, Chung UI, Kawaguchi H
  • 雑誌名: J Biol Chem 巻: 288 ページ: 28620-9
• [雑誌論文] Cell-sheet technology combined with a thienoindazole derivative small compound TD-198946 for cartilage regeneration (2013)
  • 著者名/発表者名: Yano F, Hojo H, Ohba S, Saito T, Honnami M, Mochizuki M, Takato T, Kawaguchi H, Chung UI
  • 雑誌名: Biomaterials 巻: 34 ページ: 5581-7
• [雑誌論文] Hedgehog-Gli activators direct osteo-chondrogenic function of bone morphogenetic protein toward osteogenesis in the perichondrium (2013)
  • 著者名/発表者名: Hojo H, Ohba S, Taniguchi K, Shirai M, Yano F, Saito T, Ikeda T, Nakajima K, Komiyama Y, Nakagata N, Suzuki K, Mishina Y, Yamada M, Konno T, Takato T, Kawaguchi H, Kambara H, Chung UI.
  • 雑誌名: J Biol Chem 巻: 288 ページ: 9924-32
• [雑誌論文] Notch signaling in chondrocytes modulates endochondral ossification and osteoarthritis development (2013)
  • 著者名/発表者名: Hosaka Y, Saito T (equally contributed), Sugita S, Hikata T, Kobayashi H, Fukai A, Taniguchi Y, Hirata M, Akiyama H, Chung UI, Kawaguchi H
  • 雑誌名: Proc Natl Acad Sci U S A 巻: 110 ページ: 1875-80
• [雑誌論文] β-catenin Regulates PTH/PTHrP Receptor Signals and Chondrocyte Hypertrophy through Binding to Its Intracellular C-terminal Region (2013)
  • 著者名/発表者名: Yano F, Saito T (equally contributed), Ogata N, Yamazawa T, Iino M, Chung UI, Kawaguchi H
  • 雑誌名: Arthritis Rheum 巻: 65 ページ: 429-35
• [雑誌論文] A novel disease-modifying osteoarthritis drug targeting Runx1 (2013)
  • 著者名/発表者名: Yano F, Hojo H, Ohba S, Fukai A, Hosaka Y, Ikeda T, Saito T, Hirata M, Chikuda H, Takato T, Kawaguchi H, Chung UI
  • 雑誌名: Ann Rheum Dis 巻: 72 ページ: 748-53
• [雑誌論文] Generation of Col2a1-EGFP iPS cells for monitoring chondrogenic differentiation (2013)
  • 著者名/発表者名: Saito T, Yano F, Mori D, Ohba S, Hojo H, Otsu M, Eto K, Nakauchi H, Tanaka S, Chung UI, Kawaguchi H
  • 雑誌名: PLoS One 巻: 16;8(9) 号: 9 ページ: e74137-e74137
  • DOI: 10.1371/journal.pone.0074137
  • 査読あり
• [雑誌論文] Transcriptional induction of ADAMTS5 protein by nuclear factor-κB (NF-κB) family member RelA/p65 in chondrocytes during osteoarthritis development. (2013)
  • 著者名/発表者名: Kobayashi H, Hirata M, Saito T, Itoh S, Chung UI, Kawaguchi H.
  • 雑誌名: J Biol Chem. 巻: 288 号: 40 ページ: 28620-9
  • DOI: 10.1074/jbc.m113.452169
  • 査読あり
• [雑誌論文] Cell-sheet technology combined with a thienoindazole derivative small comnound TD-198946 for cartilage regeneration (2013)
  • 著者名/発表者名: Yano F, Hojo H, et al.
  • 雑誌名: Biomaterials 巻: 34 号: 22 ページ: 5581-5587
  • DOI: 10.1016/j.biomaterials.2013.04.008
  • 査読あり
• [雑誌論文] Hedgehog-Gli activators direct osteo-chondrogenic function of bone morp hogenetic protein toward osteogenesis in the perichondrium. (2013)
  • 著者名/発表者名: Hojo H, et al.
  • 雑誌名: J Biol Chem 巻: 288 号: 14 ページ: 9924-9932
  • DOI: 10.1074/jbc.m112.409342
  • 査読あり
• [雑誌論文] A novel disease-modifying osteoarthritis drug candidate targeting Runx1 (2013)
  • 著者名/発表者名: Yano, F. et al.
  • 雑誌名: Ann Rheum Dis. 巻: 72 号: 5 ページ: 748
  • DOI: 10.1136/annrheumdis-2012-201745
  • 査読あり
• [雑誌論文] Notch signaling in chondrocytes modulates endochondral ossification and osteoarthritis development. (2013)
  • 著者名/発表者名: Hosaka Y, Saito T (equally contributed), et al.
  • 雑誌名: Proc Natl Acad Sci U S A. 巻: 110 ページ: 1875-1880
  • 査読あり
• [雑誌論文] Physical performance, bone and joint diseases, and incidence of falls in Japanese men and women: A longitudinal cohort study. (2013)
  • 著者名/発表者名: Muraki S, Kawaguchi H, et al.
  • 雑誌名: Osteoporosis Int 巻: 24 ページ: 459-466
  • 査読あり
• [雑誌論文] A novel disease-modifying osteoarthritis drug candidate targeting Runx1. (2013)
  • 著者名/発表者名: Yano F, Chikuda H, et al.
  • 雑誌名: Ann Rheum Dis 巻: 72 ページ: 748-753
  • 査読あり
• [雑誌論文] β-catenin regulates PTH/PTHrP receptor signals and chondrocyte hypertrophy through binding to its intracellular C-terminal region (2013)
  • 著者名/発表者名: Yano F, Kawaguchi H, et al.
  • 雑誌名: Arthritis Rheum 巻: 65 ページ: 429-435
  • 査読あり
• [雑誌論文] Radiographical risk factors for major intraoperative blood loss during laminoplasty in patients with ossification of the posterior longitudinal ligament (2012)
  • 著者名/発表者名: Kato S, Chikuda H, Seichi A, Ohtsu H, Kimura A, Toyama Y
  • 雑誌名: Spine (Phila Pa 1976) 巻: 37(25)
• [雑誌論文] Mortality and morbidity in dialysis-dependent patients undergoing spinal surgery : analysis of a national administrative database in Japan (2012)
  • 著者名/発表者名: Chikuda H, Yasunaga H, Horiguchi H, Takeshita K, Kawaguchi H, Matsuda S, Nakamura K
  • 雑誌名: J Bone Joint Surg Am 巻: 94(5) ページ: 433-8
• [雑誌論文] Normative score and cut-off value of the Neck Disability Index (2012)
  • 著者名/発表者名: Kato S, Takeshita K, Matsudaira K, Tonosu J, Hara N, Chikuda H
  • 雑誌名: J Orthop Sci 巻: 17(6) ページ: 687-93
• [雑誌論文] Gli1 Protein Participates in Hedgehog-mediated Specification of Osteoblast Lineage during Endochondral Ossification (2012)
  • 著者名/発表者名: Hojo H, Ohba S, Yano F, Saito T, Ikeda T, Nakajima K, Komiyama Y, Nakagata N, Suzuki K, Takato T, Kawaguchi H, Chung UI
  • 雑誌名: J Biol Chem 巻: 287 ページ: 17860-9
• [雑誌論文] GSK-3α and GSK-3β proteins are involved in early stages of chondrocyte differentiation with functional redundancy through RelA protein phosphorylation (2012)
  • 著者名/発表者名: Itoh S, Saito T, Hirata M, Ushita M, Ikeda T, Woodgett JR, Algül H, Schmid RM, Chung UI, Kawaguchi H
  • 雑誌名: J Biol Chem 巻: 287 ページ: 29227-36
• [雑誌論文] C/EBPβ and RUNX2 cooperate to degrade cartilage with MMP-13 as the target and HIF-2α as the inducer in chondrocytes (2012)
  • 著者名/発表者名: Hirata M, Kugimiya F, Fukai A, Saito T, Yano F, Ikeda T, Mabuchi A, Sapkota BR, Akune T, Nishida N, Yoshimura N, Nakagawa T, Tokunaga K, Nakamura K, Chung UI, Kawaguchi H
  • 雑誌名: Hum Mol Genet 巻: 21 ページ: 1111-23
• [雑誌論文] Lack of a chondroprotective effect of cyclooxygenase 2 inhibition in a surgically induced model of osteoarthritis in mice (2012)
  • 著者名/発表者名: Fukai A, Kamekura S, Chikazu D, Nakagawa T, Hirata M, Saito T, Hosaka Y, Ikeda T, Nakamura K, Chung UI, Kawaguchi H
  • 雑誌名: Arthritis Rheum 巻: 64 ページ: 198-203
• [雑誌論文] Mortality and morbidity in dialysis-dependent patients undergoing spinal surgery: analysis of a national administrative database in Japan. (2012)
  • 著者名/発表者名: Chikuda H, et al.
  • 雑誌名: J Bone Joint Surg Am. 巻: 94 ページ: 433-438
  • 査読あり
• [雑誌論文] Lack of a chondroprotective effect of cyclooxygenase 2 inhibition in a surgically induced model of osteoarthritis in mice. (2012)
  • 著者名/発表者名: Fukai A, Kawaguchi H, et al.
  • 雑誌名: Arthritis Rheum 巻: 64 ページ: 198-203
  • 査読あり
• [雑誌論文] C/EBP-β and RUNX2 cooperate to degrade cartilage with MMP-13 as the target and HIF-2α as the inducer in chondrocytes. (2012)
  • 著者名/発表者名: Hirata M, Kawaguchi H, et al.
  • 雑誌名: Hum Mol Genet 巻: 21 ページ: 1111-1123
  • 査読あり
• [雑誌論文] Incidence and risk factors for radiographic knee osteoarthritis and knee pain in Japanese men and women: A longitudinal population-based cohort study. (2012)
  • 著者名/発表者名: Muraki S, Kawaguchi H, et al.
  • 雑誌名: Arthritis Rheum 巻: 64 ページ: 1447-1456
  • 査読あり
• [雑誌論文] Incidence and risk factors for radiographic lumbar spondylosis and lower back pain in Japanese men and women: The ROAD study. (2012)
  • 著者名/発表者名: Muraki S, Kawaguchi H, et al.
  • 雑誌名: Osteoarthr Cartilage 巻: 20 ページ: 712-718
  • 査読あり
• [雑誌論文] GSK-3α and GSK-3β are involved in early stages of chondrocyte differentiation with functional redundancy through RelA phosphorylation. (2012)
  • 著者名/発表者名: Itoh S, Kawaguchi H, et al.
  • 雑誌名: J Biol Chem 巻: 287 ページ: 29227-28236
  • 査読あり
• [雑誌論文] Prevalence of symptomatic lumbar spinal stenosis and its association with physical performance in a population-based cohort in Japan: The Wakayama Spine Study. (2012)
  • 著者名/発表者名: Ishimoto Y, Kawaguchi H, et al.
  • 雑誌名: Osteoarthritis Cartilage 巻: 20 ページ: 1103-1108
  • 査読あり
• [雑誌論文] Prevalence of cervical cord compression and its association with physical performance in a population-based cohort in Japan: The Wakayama Spine Study. (2012)
  • 著者名/発表者名: Nagata K, Kawaguchi H, et al.
  • 雑誌名: Spine 巻: 37 ページ: 1892-1898
  • NAID: 10031169860
  • 査読あり
• [雑誌論文] Incidence and risk factors for radiographic knee osteoarthritis and knee pain in Japanese men and women : A longitudinal population-based cohort study (2012)
  • 著者名/発表者名: Muraki S, Kawaguchi H, et al.
  • 雑誌名: Arthritis Rheum 巻: (E-pub)
  • 査読あり
• [雑誌論文] Mortality and morbidity in dialysis-dependent patients undergoing spinal surgery : analysis of a national administrative database in Japan (2012)
  • 著者名/発表者名: Chikuda H, et al.
  • 雑誌名: J Bone Joint Surg Am 巻: 94 ページ: 433-8
  • 査読あり
• [雑誌論文] The normative score and the cut-off value of the Oswestry Disability Index (ODI) (2012)
  • 著者名/発表者名: Tonosu J, Chikuda H, et al.
  • 雑誌名: Eur Spine J 巻: (E-pub)
  • 査読あり
• [雑誌論文] Reference values for hand grip strength, muscle mass, walking time, and one-leg standing time as indices for locomotive syndrome and associated disability : the second survey of the ROAD study (2011)
  • 著者名/発表者名: Yoshimura N, Kawaguchi H, et al.
  • 雑誌名: J Orthop Sci 巻: 16 ページ: 768-77
  • 査読あり
• [雑誌論文] Independent association of joint space narrowing and osteophyte formation at the knee with health-related quality of life in Japan : a cross-sectional study (2011)
  • 著者名/発表者名: Muraki S, Kawaguchi H, et al.
  • 雑誌名: Arthritis Rheum 巻: 63 ページ: 3859-64
  • 査読あり
• [雑誌論文] Prevalence of falls and the association with knee osteoarthritis and lumbar spondylosis as well as knee and lower back pain in Japanese men and women (2011)
  • 著者名/発表者名: Muraki S, Kawaguchi H, et al.
  • 雑誌名: Arthritis Care Res 巻: 63 ページ: 1425-31
  • 査読あり
• [雑誌論文] Changes in serum levels of biochemical markers of bone turnover during 10 years among Japanese men and women : associated factors and birth-cohort effect. The Taiji Study (2011)
  • 著者名/発表者名: Yoshimura N, Kawaguchi H, et al.
  • 雑誌名: J Bone Miner Metab. 巻: 29 ページ: 699-708
  • NAID: 10030895205
  • 査読あり
• [雑誌論文] Health-related quality of life in subjects with low back pain and knee pain in a population-based cohort study of Japanese men : the Research on Osteoarthritis Against Disability study (2011)
  • 著者名/発表者名: Muraki S, Kawaguchi H, et al.
  • 雑誌名: Spine 巻: 36 ページ: 1312-9
  • NAID: 10030716059
  • 査読あり
• [雑誌論文] Biochemical markers of bone turnover as predictors of osteoporosis and osteoporotic fractures in men and women : 10-year follow-up of the Taiji cohort (2011)
  • 著者名/発表者名: Yoshimura N, Kawaguchi H, et al.
  • 雑誌名: Mod Rheumatol 巻: 21 ページ: 608-20
  • NAID: 10030206069
  • 査読あり
• [雑誌論文] G alpha(q) signal in osteoblasts is inhibitory to the osteoanabolic action of parathyroid hormone (2011)
  • 著者名/発表者名: Ogata N, Kawaguchi H, et al.
  • 雑誌名: J Biol Chem 巻: 286 ページ: 13733-40
  • 査読あり
• [雑誌論文] Ossification of the posterior atlantoaxial membrane associated with an os odontoideum : a case report (2011)
  • 著者名/発表者名: Ohya J, Chikuda H, et al.
  • 雑誌名: J Orthop Surg 巻: 19 ページ: 392-4
  • 査読あり
• [雑誌論文] Use of Doppler ultrasonography to detect an elusive communication of a spinal extradural arachnoid cyst (2011)
  • 著者名/発表者名: Kanetaka M, Chikuda H, et al.
  • 雑誌名: J Clin Neurosci 巻: 18 ページ: 863-4
  • 査読あり
• [雑誌論文] Acute cervical spinal cord injury complicated by preexisting ossification of the posterior longitudinal ligament : a multicenter study (2011)
  • 著者名/発表者名: Chikuda H, et al.
  • 雑誌名: Spine 巻: 36 ページ: 1453-8
  • NAID: 10030716761
  • 査読あり
• [学会発表] Rbpj-dependent Notch signaling in chondrocytes modulates endochondral ossification during osteoarthritis development through transcriptional induction by Hes1 (2012)
  • 著者名/発表者名: Sugita S, Hosaka Y, Kawaguchi H, et al
  • 学会等名: American Society for Bone and Mineral Research (ASBMR)
  • 発表場所: Minneaplis, Minnesota, USA
  • 年月日: 2012-10-12
• [学会発表] NF-/κBファミリーRelAは、ADAMTS5の転写誘導因子として変形性関節症の進行に作用する (2012)
  • 著者名/発表者名: 小林寛、川口浩, 他
  • 学会等名: 日本軟骨代謝学会
  • 発表場所: 名古屋
  • 年月日: 2012-09-03
• [学会発表] RBPjκ-dependent Notch signaling in chondrocytes modulates skeletal growth and osteoarthritis development (2012)
  • 著者名/発表者名: Hosaka Y, Kawaguchi H, et al
  • 学会等名: Cold Spring Harbor Asia Conference
  • 発表場所: Suzhou, China
  • 年月日: 2012-06-11
• [学会発表] Notch/Rbpl/Hes1 signal in chondrocytes modulates osteoarthritis development (2012)
  • 著者名/発表者名: Sugita S, Hosaka Y, Kawaguchi H, et al
  • 学会等名: World Congress on Osteoarthritis (OARSI)
  • 発表場所: Barcelona, Spain
  • 年月日: 2012-04-26
• [学会発表] Notch/Rbpl/Hes1 signal in chondrocytes modulates osteoarthritis development. (2012)
  • 著者名/発表者名: Sugita S, Hosaka Y, Kawaguchi H, et al.
  • 学会等名: World Congress on Osteoarthritis (OARSI)
  • 発表場所: Barcelona, Spain
• [学会発表] RBPjκ-dependent Notch signaling in chondrocytes modulates skeletal growth and osteoarthritis development. (2012)
  • 著者名/発表者名: Hosaka Y, Kawaguchi H, et al
  • 学会等名: Cold Spring Harbor Asia Conference
  • 発表場所: Suzhou, China
• [学会発表] Rbpj-dependent Notch signaling in chondrocytes modulates endochondral ossification during osteoarthritis development through transcriptional induction by Hes1. (2012)
  • 著者名/発表者名: Sugita S, Hosaka Y, Kawaguchi H, et al.
  • 学会等名: American Society for Bone and Mineral Research (ASBMR)
  • 発表場所: Minneaplis, Minnesota, USA
• [学会発表] C/EBPb and RUNX2 Cooperatively Control Cartilage Degradation with MMP-13 as the Target and HIF-2a as the Inducer in Chondrocytes (2011)
  • 著者名/発表者名: Hirata M, Kawaguchi H, et al.
  • 学会等名: The American Society for Bone and Mineral Research (ASBMR)
  • 発表場所: San Diego, USA
  • 年月日: 2011-09-17
• [学会発表] Notch/Rbpj/Hes1 Signal in Chondrocytes Modulates the Terminal Stage of Endochondral Ossification during Skeletal Growth and Osteoarthritis Development (2011)
  • 著者名/発表者名: Hosaka Y, Kawaguchi H, et al.
  • 学会等名: The American Society for Bone and Mineral Research (ASBMR)
  • 発表場所: San Diego, USA
  • 年月日: 2011-09-17
• [学会発表] Functional Redundancy of GSK-3α and GSK-3β to Control Chondrocyte Differentiation through Phosphorylation of RelA/NF-κB p65 (2011)
  • 著者名/発表者名: Itoh S, Kawaguchi H, et al.
  • 学会等名: Osteoarthritis Research Society International (OARSI)
  • 発表場所: San Diego, USA
  • 年月日: 2011-09-16
• [学会発表] Transcriptional induction of ADAMTS5 by NF-κB family member RelA/p65 in chondrocytes during osteoarthritis development (2011)
  • 著者名/発表者名: Kobayashi H, Kawaguchi H, et al.
  • 学会等名: International Osteoporosis Federation/Australian and New Zealand Bone & Mineral Society (IOF/ANZBMS)
  • 発表場所: Gold coast (AUS)
  • 年月日: 2011-09-07
• [学会発表] NF-κBファミリーRelAは、ADAMTS5の転写誘導因子として変形性関節症の進行に作用する (2011)
  • 著者名/発表者名: 小林寛、川口浩, 他
  • 学会等名: 日本骨代謝学会
  • 発表場所: 大阪
  • 年月日: 2011-07-30
• [学会発表] 軟骨細胞のNotch/Rbpj/Hes1シグナルは骨格形成および変形性関節症における軟骨内骨化の後期過程を制御する (2011)
  • 著者名/発表者名: 保坂陽子、川口浩, 他
  • 学会等名: 日本骨代謝学会
  • 発表場所: 大阪
  • 年月日: 2011-07-30
• [学会発表] GSK-3αとGSK-3βは協調的にRelA/NF-κB p65のリン酸化を介して軟骨細胞初期分化を制御する (2011)
  • 著者名/発表者名: 伊藤祥三、川口浩, 他
  • 学会等名: 日本骨代謝学会
  • 発表場所: 大阪
  • 年月日: 2011-07-29
• [備考] 東京大学 整形外科・脊椎外科
  • URL: http://www.u-tokyo-ortho.jp/
• [備考]
  • URL: http://www.h.u-tokyo.ac.jp/ortho/