1. Academic Validation
  2. 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.
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