Strategic approach for cartilage degeneration based on functional analysis of susceptibility gene
| Project/Area Number |
20390395
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Orthopaedic surgery
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| Research Institution | University of Toyama |
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Principal Investigator |
TOMOATSU Kimura 富山大学, 大学院・医学薬学研究部(医学), 教授 (80167379)
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| Co-Investigator(Kenkyū-buntansha) |
KAWAGUCHI Yoshiharu 富山大学, 大学院・医学薬学研究部(医学), 准教授 (00262527)
SEKI Shoji 富山大学, 大学院・医学薬学研究部(医学), 助教 (00432112)
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| Project Period (FY) |
2008 – 2010
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| Project Status |
Completed (Fiscal Year 2010)
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| Budget Amount *help |
¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000)
Fiscal Year 2010: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2009: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2008: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
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| Keywords | 関節病学 / 軟骨 / 感受性遺伝子 / 椎間板 / 変性 / 疾患感受性遺伝子 / 環境因子 |
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| Research Abstract |
To clarify the in vivo function of CILP, which was identified as a susceptibility gene associated with cartilage degenerative disease, we firstly established conditional Tg mouse line expressing the gene specifically in cartilage or nucleus pulposus. X-ray, MRI and histochemical analysis of the mice lines indicated that the specific overexpression of the CILP in the nucleus pulposus was responsible for the accelerated intervertebral disc degeneration. This was apparently caused by in vivo binding of the TGFβwith CILP, reduced receptor binding and TGF. signaling that leads to the inhibition of the cartilage matrix gene expression. In addition there was enhanced matrix proteinase expression and disc cell apoptosis that also generated matrix homeostasis imbalance. Based on these observations, we then tried to block the factors associated with the CILP signaling pathway. Inhibition of aggrecanase by injection of ADAMTS5 siRNA in vivo using intervertebral disc degeneration model resulted in the protection of the progression. We also started to block the upstream signal of c-fos/AP-1 using newly developed specific inhibitor. Administration of the c-fos/AP-1 inhibitor to mouse DMM model dramatically prevented the progression of articular cartilage degeneration, partly through inhibition of proteinase expression. Thus, these observations suggested possible strategic targets for cartilage degeneration.
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Report
(4 results)
Research Products
(32 results)
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[Journal Article] Ionizing radiation enhances tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)-induced apoptosis through up-regulations of death receptor 4(DR4) and death receptor 5(DR5) in human osteosarcoma cells2010
Author(s)
Hori T, Kondo T, Kanamori M, Tabuchi Y, Ogawa R, Zhao QL, Ahmed K, Yasuda T, Seki S, Suzuki K, Kimura T.
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Journal Title
J Orthop Res
Volume: 28
Pages: 739-745
Related Report
Peer Reviewed
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[Journal Article] Nutlin-3 enhances tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)-induced apoptosis through up-regulation of death receptor 5(DR5) in human sarcoma HOS cells and human colon cancer HCT116 cells2010
Author(s)
Hori T, Kondo T, Kanamori M, Tabuchi Y, Ogawa R, Zhao QL, Ahmed K, Yasuda T, Seki S, Suzuki K, Kimura T.
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Journal Title
Cancer Lett
Volume: 287
Pages: 98-108
Related Report
Peer Reviewed
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[Journal Article] Specificity of fusion genes in adipocytic tumors2010
Author(s)
Kubo T, Matsui Y, Naka N, Araki N, Myoui A, Endo K, Yasui N, Ohtani O, Suzuki K, Kimura T, Yoshikawa H, Ueda T.
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Journal Title
Anticancer Res
Volume: 30
Pages: 661-664
Related Report
Peer Reviewed
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[Journal Article] PDGF receptorβis a potent regulator of mesenchymal stromal cell function2008
Author(s)
Tokunaga A, Oya T, Ishii Y, Motomura H, Nakamura C, Ishizawa S, Fujimori T, Nabeshima Y, Umezawa A, Kanamori M, Kimura T, Sasahara M.
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Journal Title
J Bone Miner Res
Volume: 23
Pages: 1519-1528
Related Report
Peer Reviewed
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[Journal Article] A functional polymorphism in THBS2 that affects alternative splicing and MMP binding is associated with lumbar-disc herniation2008
Author(s)
Hirose Y, Chiba K, Karasugi T, Nakajima M, Kawaguchi Y, Mikami Y, Furuichi T, Mio F, Miyake A, Miyamoto T, Ozaki K, Takahashi A, Mizuta H, Kubo T, Kimura T, Tanaka T, Toyama Y, Ikegawa S.
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Journal Title
Am J Hum Genet
Volume: 82
Pages: 1122-1129
Related Report
Peer Reviewed
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[Presentation] CILP, cartilage intermediate layer protein, promotes lumbar disc degeneration2010
Author(s)
Seki S, Tsumaki N, Kawaguchi Y, Abe Y, Suzuki K, Iwai A, Oya T, Ikegawa S, Kimura T.
Organizer
56^<th> Annual Meeting of the Orthopaedic Research Society
Place of Presentation
New Orleans
Related Report
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[Presentation] A functional polymorphism in COL11A1 is associated with susceptibility to lumbar disc herniation2009
Author(s)
Mio F, Chiba K, Kawaguchi Y, Mikami Y, Seki S, Mori M, Hirose Y, Kubo T, Kimura T, Toyama Y, Ikegawa S.
Organizer
5^<th> Annual Meeting of the Orthopaedic Research Society
Place of Presentation
Las Vegas
Related Report
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