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
  • 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. [email protected].
  • 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.

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