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The intervertebral disc contains intrinsic circadian clocks that are regulated by age and cytokines and linked to degeneration
  1. Michal Dudek1,2,
  2. Nan Yang1,2,
  3. Jayalath PD Ruckshanthi1,2,
  4. Jack Williams1,2,
  5. Elzbieta Borysiewicz1,
  6. Ping Wang1,
  7. Antony Adamson1,
  8. Jian Li1,
  9. John F Bateman3,
  10. Michael R White1,
  11. Raymond P Boot-Handford2,
  12. Judith A Hoyland4,5,
  13. Qing-Jun Meng1,2
  1. 1Faculty of Life Sciences, University of Manchester, Manchester, UK
  2. 2Wellcome Trust Centre for Cell Matrix Research, University of Manchester, Manchester, UK
  3. 3Murdoch Children's Research Institute, Parkville, Victoria, Australia
  4. 4Faculty of Medical and Human Sciences, Centre for Tissue Injury and Repair, University of Manchester, Manchester, UK
  5. 5NIHR Manchester Musculoskeletal Biomedical Research Unit, Manchester Academic Health Science Centre, Manchester, UK
  1. Correspondence to Dr Qing-Jun Meng, Faculty of Life Sciences, University of Manchester, A.V. Hill Building, Oxford Road, Manchester M13 9PT, UK; qing-jun.meng{at}manchester.ac.uk and Professor Judith A Hoyland, Centre for Tissue Injury and Repair, Faculty of Medical and Human Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK; judith.a.hoyland{at}manchester.ac.uk

Abstract

Objectives The circadian clocks are internal timing mechanisms that drive ∼24-hour rhythms in a tissue-specific manner. Many aspects of the physiology of the intervertebral disc (IVD) show clear diurnal rhythms. However, it is unknown whether IVD tissue contains functional circadian clocks and if so, how their dysregulation is implicated in IVD degeneration.

Methods Clock gene dynamics in ex vivo IVD explants (from PER2:: luciferase (LUC) reporter mice) and human disc cells (transduced with lentivirus containing Per2::luc reporters) were monitored in real time by bioluminescence photon counting and imaging. Temporal gene expression changes were studied by RNAseq and quantitative reverse transcription (qRT)-PCR. IVD pathology was evaluated by histology in a mouse model with tissue-specific deletion of the core clock gene Bmal1.

Results Here we show the existence of the circadian rhythm in mouse IVD tissue and human disc cells. This rhythm is dampened with ageing in mice and can be abolished by treatment with interleukin-1β but not tumour necrosis factor α. Time-series RNAseq revealed 607 genes with 24-hour patterns of expression representing several essential pathways in IVD physiology. Mice with conditional knockout of Bmal1 in their disc cells demonstrated age-related degeneration of IVDs.

Conclusions We have established autonomous circadian clocks in mouse and human IVD cells which respond to age and cytokines, and control key pathways involved in the homeostasis of IVDs. Genetic disruption to the mouse IVD molecular clock predisposes to IVD degeneration. These results support the concept that disruptions to circadian rhythms may be a risk factor for degenerative IVD disease and low back pain.

  • Low Back Pain
  • Cytokines
  • Arthritis
  • Chondrocytes

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

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