Research of Notch signal in pathophysiology and therapeutics of osteoarthritis

2013 Fiscal Year Final Research Report

• Project/Area Number: 23390358
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: The University of Tokyo
• Principal Investigator: CHIKUDA Hirotaka 東京大学, 医学部附属病院, 講師 (30345219)
• Co-Investigator(Kenkyū-buntansha): KAWAGUCHI Hiroshi 東京大学, 医学部附属病院, 届出診療医 (40282660) ; OHASHI Satoru 東京大学, 医学部附属病院, 助教 (20466767)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: 関節軟骨 / 変形性関節症 / Notchシグナル

Research Abstract

Notch signaling consists of 5 ligands and 4 receptors (Notch1-4). Upon ligand binding, the Notch receptor is cleaved and its intracellular domain (ICD) translocates to the nucleus, where it binds to Rbpj, a transcription repressor, and activates expression of target genes including Hes/Hey family member. Notch1 and 2 were expressed in mouse and human articular chondrocytes, and their ICDs were translocated to the nucleus with cartilage degradation. When we deleted Rbpj in chondrocytes after skeletal growth using tamoxifen-inducible Cre mice and created an experimental OA model, cartilage degradation and Mmp13 expression were suppressed. We further investigated functions of Hes1, only target gene expressed abundantly in chondrocytes, using Hes1-flox mice. When we deleted Hes1 in the same way, OA development was suppressed while skeletal development was not affected.

Research Products

• [Journal Article] Morphological characteristics of cervical spine in patients with athetoid cerebral palsy and the accuracy of pedicle screw placement (2014)
  • Author(s): Kato S, Shoda N, Chikuda H, Seichi A, Takeshita K
  • Journal Title: Spine Volume: 39(8) Pages: E508-13
• [Journal Article] Identification of fibroblast growth factor-18 as a molecule to protect adult articular cartilage by gene expression profiling (2014)
  • Author(s): Mori Y, Saito T, Chang SH, Kobayashi H, Ladel CH, Guehring H, Chung UI, Kawaguchi H
  • Journal Title: J Biol Chem Volume: 289 Pages: 10192-200
• [Journal Article] Incidence and risk factors for mortality of vertebral osteomyelitis : a retrospective analysis using the Japanese diagnosis procedure combination database (2013)
  • Author(s): Akiyama T, Chikuda H, Yasunaga H, Horiguchi H, Fushimi K, Saita K
  • Journal Title: BMJ Open Volume: 3(3)
• [Journal Article] Generation of Col2a1-EGFP-iPS cells for monitoring chondrogenic differentiation (2013)
  • Author(s): Saito T, Yano F, Mori D, Ohba S, Hojo H, Otsu M, Eto K, Nakauchi H, Tanaka S, Chung UI, Kawaguchi H
  • Journal Title: PLoS ONE Volume: 8 Pages: e74137
• [Journal Article] Transcriptional induction of ADAMTS5 by an NF-κB family member RelA/p65 in chondrocytes during osteoarthritis development (2013)
  • Author(s): Kobayashi H, Hirata M, Saito T, Itoh S, Chung UI, Kawaguchi H
  • Journal Title: J Biol Chem Volume: 288 Pages: 28620-9
• [Journal Article] Cell-sheet technology combined with a thienoindazole derivative small compound TD-198946 for cartilage regeneration (2013)
  • Author(s): Yano F, Hojo H, Ohba S, Saito T, Honnami M, Mochizuki M, Takato T, Kawaguchi H, Chung UI
  • Journal Title: Biomaterials Volume: 34 Pages: 5581-7
• [Journal Article] Hedgehog-Gli activators direct osteo-chondrogenic function of bone morphogenetic protein toward osteogenesis in the perichondrium (2013)
  • Author(s): 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.
  • Journal Title: J Biol Chem Volume: 288 Pages: 9924-32
• [Journal Article] Notch signaling in chondrocytes modulates endochondral ossification and osteoarthritis development (2013)
  • Author(s): Hosaka Y, Saito T (equally contributed), Sugita S, Hikata T, Kobayashi H, Fukai A, Taniguchi Y, Hirata M, Akiyama H, Chung UI, Kawaguchi H
  • Journal Title: Proc Natl Acad Sci U S A Volume: 110 Pages: 1875-80
• [Journal Article] β-catenin Regulates PTH/PTHrP Receptor Signals and Chondrocyte Hypertrophy through Binding to Its Intracellular C-terminal Region (2013)
  • Author(s): Yano F, Saito T (equally contributed), Ogata N, Yamazawa T, Iino M, Chung UI, Kawaguchi H
  • Journal Title: Arthritis Rheum Volume: 65 Pages: 429-35
• [Journal Article] A novel disease-modifying osteoarthritis drug targeting Runx1 (2013)
  • Author(s): Yano F, Hojo H, Ohba S, Fukai A, Hosaka Y, Ikeda T, Saito T, Hirata M, Chikuda H, Takato T, Kawaguchi H, Chung UI
  • Journal Title: Ann Rheum Dis Volume: 72 Pages: 748-53
• [Journal Article] Radiographical risk factors for major intraoperative blood loss during laminoplasty in patients with ossification of the posterior longitudinal ligament (2012)
  • Author(s): Kato S, Chikuda H, Seichi A, Ohtsu H, Kimura A, Toyama Y
  • Journal Title: Spine (Phila Pa 1976) Volume: 37(25) Pages: E1588-93
• [Journal Article] Mortality and morbidity in dialysis-dependent patients undergoing spinal surgery : analysis of a national administrative database in Japan (2012)
  • Author(s): Chikuda H, Yasunaga H, Horiguchi H, Takeshita K, Kawaguchi H, Matsuda S, Nakamura K
  • Journal Title: J Bone Joint Surg Am Volume: 94(5) Pages: 433-8
• [Journal Article] Normative score and cut-off value of the Neck Disability Index (2012)
  • Author(s): Kato S, Takeshita K, Matsudaira K, Tonosu J, Hara N, Chikuda H
  • Journal Title: J Orthop Sci Volume: 17(6) Pages: 687-93
• [Journal Article] Gli1 Protein Participates in Hedgehog-mediated Specification of Osteoblast Lineage during Endochondral Ossification (2012)
  • Author(s): Hojo H, Ohba S, Yano F, Saito T, Ikeda T, Nakajima K, Komiyama Y, Nakagata N, Suzuki K, Takato T, Kawaguchi H, Chung UI
  • Journal Title: J Biol Chem Volume: 287 Pages: 17860-9
• [Journal Article] GSK-3α and GSK-3β proteins are involved in early stages of chondrocyte differentiation with functional redundancy through RelA protein phosphorylation (2012)
  • Author(s): Itoh S, Saito T, Hirata M, Ushita M, Ikeda T, Woodgett JR, Algül H, Schmid RM, Chung UI, Kawaguchi H
  • Journal Title: J Biol Chem Volume: 287 Pages: 29227-36
• [Journal Article] C/EBPβ and RUNX2 cooperate to degrade cartilage with MMP-13 as the target and HIF-2α as the inducer in chondrocytes (2012)
  • Author(s): 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
  • Journal Title: Hum Mol Genet Volume: 21 Pages: 1111-23
• [Journal Article] Lack of a chondroprotective effect of cyclooxygenase 2 inhibition in a surgically induced model of osteoarthritis in mice (2012)
  • Author(s): Fukai A, Kamekura S, Chikazu D, Nakagawa T, Hirata M, Saito T, Hosaka Y, Ikeda T, Nakamura K, Chung UI, Kawaguchi H
  • Journal Title: Arthritis Rheum Volume: 64 Pages: 198-203
• [Presentation] Rbpj-dependent Notch signaling in chondrocytes modulates endochondral ossification during osteoarthritis development through transcriptional induction by Hes1 (2012)
  • Author(s): Sugita S, Hosaka Y, Kawaguchi H, et al
  • Organizer: American Society for Bone and Mineral Research (ASBMR)
  • Place of Presentation: Minneaplis, Minnesota, USA
  • Year and Date: 2012-10-12
• [Presentation] RBPjκ-dependent Notch signaling in chondrocytes modulates skeletal growth and osteoarthritis development (2012)
  • Author(s): Hosaka Y, Kawaguchi H, et al
  • Organizer: Cold Spring Harbor Asia Conference
  • Place of Presentation: Suzhou, China
  • Year and Date: 2012-06-11
• [Presentation] Notch/Rbpl/Hes1 signal in chondrocytes modulates osteoarthritis development (2012)
  • Author(s): Sugita S, Hosaka Y, Kawaguchi H, et al
  • Organizer: World Congress on Osteoarthritis (OARSI)
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2012-04-26