2. Academic Validation
  3. A selective inhibition of c-Fos/activator protein-1 as a potential therapeutic target for intervertebral disc degeneration and associated pain

A selective inhibition of c-Fos/activator protein-1 as a potential therapeutic target for intervertebral disc degeneration and associated pain

  • Sci Rep. 2017 Dec 5;7(1):16983. doi: 10.1038/s41598-017-17289-y.
Hiroto Makino 1,  Shoji Seki 2,  Yasuhito Yahara 1,  Shunichi Shiozawa 3,  Yukihiko Aikawa 4,  Hiraku Motomura 1,  Makiko Nogami 1,  Kenta Watanabe 1,  Takeshi Sainoh 5,  Hisakatsu Ito 6,  Noriyuki Tsumaki 7,  Yoshiharu Kawaguchi 1,  Mitsuaki Yamazaki 6,  Tomoatsu Kimura 1
Affiliations

Affiliations

  • 1 Department of Orthopaedic Surgery, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
  • 2 Department of Orthopaedic Surgery, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan. seki@med.u-toyama.ac.jp.
  • 3 Department of Internal Medicine, Kyushu University Beppu Hospital, 4546 Tsurumihara, Tsurumiji, Beppu, Oita, 874-0838, Japan.
  • 4 Toyama Chemical Co., Ltd., 4-1 Shimookui 2-chome, Toyama, 930-8508, Japan.
  • 5 Department of Orthopaedic Surgery, Sainou Hospital, 70 Takata, Toyama, 930-0866, Japan.
  • 6 Department of Anesthesiology, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
  • 7 Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
PMID: 29208967 DOI: 10.1038/s41598-017-17289-y
Abstract

Intervertebral disc (IVD) degeneration is a major cause of low back pain. The transcription factor c-Fos/Activator Protein-1 (AP-1) controls the expression of inflammatory cytokines and Matrix Metalloproteinases (MMPs) that contribute to the pathogenesis IVD degeneration. We investigated the effects of inhibition of c-Fos/AP-1 on IVD degeneration and associated pain. A selective inhibitor, T-5224, significantly suppressed the interleukin-1β-induced up-regulation of MMP-3, MMP-13 and Adamts-5 transcription in human nucleus pulposus cells and in a mouse explant culture model of IVD degeneration. We used a tail disc percutaneous needle puncture method to further assess the effects of oral administration of T-5224 on IVD degeneration. Analysis of disc height, T2-magnetic resonance imaging (MRI) findings, and histology revealed that IVD degeneration was significantly mitigated by T-5224. Further, oral administration of T-5224 ameliorated pain as indicated by the extended tail-flick latency in response to heat stimulation of rats with needle-puncture-induced IVD degeneration. These findings suggest that the inhibition of c-Fos/AP-1 prevents disc degeneration and its associated pain and that T-5224 may serve as a drug for the prevention of IVD degeneration.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12270
    99.59%, c-Fos/AP-1抑制剂
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