Environmental Disruption of Circadian Rhythm Predisposes Mice to Osteoarthritis-Like Changes in Knee Joint

Ranjan Kc, Xin Li, Robin M. Voigt, Michael B. Ellman, Keith C. Summa, Martha Hotz Vitaterna, Ali Keshavarizian, Fred W. Turek, Qing Jun Meng, Gary S. Stein, Andre J. van Wijnen, Di Chen, Christopher B. Forsyth*, Hee Jeong Im

*Corresponding author for this work

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Circadian rhythm dysfunction is linked to many diseases, yet pathophysiological roles in articular cartilage homeostasis and degenerative joint disease including osteoarthritis (OA) remains to be investigated in vivo. Here, we tested whether environmental or genetic disruption of circadian homeostasis predisposes to OA-like pathological changes. Male mice were examined for circadian locomotor activity upon changes in the light:dark (LD) cycle or genetic disruption of circadian rhythms. Wild-type (WT) mice were maintained on a constant 12h:12h LD cycle (12:12 LD) or exposed to weekly 12h phase shifts. Alternatively, male circadian mutant mice (ClockΔ19 or Csnk1etau mutants) were compared with age-matched WT littermates that were maintained on a constant 12:12 LD cycle. Disruption of circadian rhythms promoted osteoarthritic changes by suppressing proteoglycan accumulation, upregulating matrix-degrading enzymes and downregulating anabolic mediators in the mouse knee joint. Mechanistically, these effects involved activation of the PKCδ-ERK-RUNX2/NFκB and β-catenin signaling pathways, stimulation of MMP-13 and ADAMTS-5, as well as suppression of the anabolic mediators SOX9 and TIMP-3 in articular chondrocytes of phase-shifted mice. Genetic disruption of circadian homeostasis does not predispose to OA-like pathological changes in joints. Our results, for the first time, provide compelling in vivo evidence that environmental disruption of circadian rhythms is a risk factor for the development of OA-like pathological changes in the mouse knee joint.

Original languageEnglish (US)
Pages (from-to)2174-2183
Number of pages10
JournalJournal of Cellular Physiology
Volume230
Issue number9
DOIs
StatePublished - Sep 1 2015

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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    Kc, R., Li, X., Voigt, R. M., Ellman, M. B., Summa, K. C., Vitaterna, M. H., Keshavarizian, A., Turek, F. W., Meng, Q. J., Stein, G. S., van Wijnen, A. J., Chen, D., Forsyth, C. B., & Im, H. J. (2015). Environmental Disruption of Circadian Rhythm Predisposes Mice to Osteoarthritis-Like Changes in Knee Joint. Journal of Cellular Physiology, 230(9), 2174-2183. https://doi.org/10.1002/jcp.24946