Analysis of molecular mechanisms maintaining homeostasis of intervertebal disc and leading to degeneration

• Project/Area Number: 25861337
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Orthopaedic surgery
• Research Institution: Keio University
• Principal Investigator: FUJITA Nobuyuki 慶應義塾大学, 医学部, 助教 (30348685)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 椎間板 / 腰椎変性疾患 / 椎間板変性 / 髄核 / HIF-1alpha / Syndecan4 / Sox9 / PHD

Outline of Final Research Achievements

The experiments described in this investigation demonstrated for the first time that in NP cells, expression of SDC4 was controlled by oxemic tension. Our studies also revealed that HIF-1alpha and not HIF-2 alpha controlled hypoxic regulation of SDC4 expression. A second major observation was that SDC4 modulated the expression of Sox9, a key transcriptional regulator of aggrecan expression in NP cells. These findings lend strong support to the hypothesis that in the hypoxic intervertebral disc, SDC4 is important in homeostatic maintenance of the NP.

Research Products

• [Journal Article] HIF-1-PHD2 axis controls expression of syndecan 4 in nucleus pulposus cells (2014)
  • Author(s): Fujita N, Hirose Y, Tran CM, Chiba K, Miyamoto T, Toyama Y, Shapiro IM, Risbud MV.
  • Journal Title: FASEB J. Volume: 28 Issue: 6 Pages: 2455-2465
  • DOI: 10.1096/fj.13-243741
  • Peer Reviewed / Open Access
• [Journal Article] Hypoxia-inducible factor (HIF)-1α and CCN2 form a regulatory circuit in hypoxic nucleus pulposus cells: CCN2 suppresses HIF-1α level and transcriptional activity. (2013)
  • Author(s): Tran CM, Fujita N, Huang BL, Ong JR, Lyons KM, Shapiro IM, Risbud MV
  • Journal Title: J Biol Chem Volume: 288 Issue: 18 Pages: 12654-12666
  • DOI: 10.1074/jbc.m112.448860
  • Peer Reviewed
• [Journal Article] Inflammatory cytokines associated with degenerative disc disease control aggrecanase-1 (ADAMTS-4) expression in nucleus pulposus cells through MAPK and NF-κB (2013)
  • Author(s): Tian Y, Yuan W, Fujita N, Wang J, Wang H, Shapiro IM, Risbud MV
  • Journal Title: Am J Pathol Volume: 182 Issue: 6 Pages: 2310-2321
  • DOI: 10.1016/j.ajpath.2013.02.037
  • Peer Reviewed
• [Presentation] Brachyury is an essential transcription factor for maintaining homeostasis in notochordal cells (2015)
  • Author(s): N. Fujita, R. Watanabe, S. Suzuki, T. Hikata, K. Watanabe, K. Ishii, T. Miyamoto, Y. Toyama, M. Matsumoto
  • Organizer: 61th Annual Meeting Orthopaedic Research Society
  • Place of Presentation: 米国ラスベガス
  • Year and Date: 2015-03-28 – 2015-03-31
• [Presentation] Reactive oxygen species are therapeutic targets for intervertebral disc degeneration (2015)
  • Author(s): S. Suzuki, N. Fujita, N. Hosogane, K. Ishii, R. Watanabe, T. Hikata K. Takubo, K. Watanabe, K. Horiuchi, Y. Toyama, T. Miyamoto, M. Matsumoto
  • Organizer: 61th Annual Meeting Orthopaedic Research Society
  • Place of Presentation: 米国ラスベガス
  • Year and Date: 2015-03-28 – 2015-03-31
• [Presentation] Follistatin-like protein 1 regulates the expression of type II collagen via BMP pathway in notochordal cells (2015)
  • Author(s): R. Watanabe, N. Fujita, S. Suzuki, T. Hikata, K. Watanabe, K. Ishii, T. Miyamoto, Y. Toyama, M. Matsumoto
  • Organizer: 61th Annual Meeting Orthopaedic Research Society
  • Place of Presentation: 米国ラスベガス
  • Year and Date: 2015-03-28 – 2015-03-31
• [Presentation] Molecular characterization of chordoma cell line U-CH1-N: Applications for intervertebral disc research (2014)
  • Author(s): N. Fujita, N. Hosogane, K. Ishii, T. Hikata, Y. Toyama, T. Miyamoto. M. Matsumoto
  • Organizer: 41th International Society for the Study of the Lumber Spine
  • Place of Presentation: 韓国ソウル
  • Year and Date: 2014-06-03 – 2014-06-07
• [Presentation] HIF-1-PHD2 Axis Controls Expression of Syndecan-4 in Hypoxic Nucleus Pulposus Cells of the Intervertebral Disc: Evidence of Context Dependent Function in Health and Disease (2014)
  • Author(s): Nobuyuki Fujita, Yuichiro Hirose, Cassie M. Tran, Kazuhiro Chiba, Takeshi Miyamoto,Yoshiaki Toyama, Irving M. Shapiro, Makarand V. Risbud
  • Organizer: 2014 ORS Annual Meeting
  • Place of Presentation: New Orleans, Louisiana
• [Presentation] 椎間板髄核細胞におけるsyndecan4の発現制御メカニズムおよび機能解析 (2013)
  • Author(s): 藤田順之, 千葉一裕, 宮本健史, 松本守雄, 戸山芳昭, Irving Shapiro, Makarand Risbud
  • Organizer: 日本整形外科学会基礎学術集会
  • Place of Presentation: 千葉