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

Research output: Contribution to journalArticle

19 Citations (Scopus)

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 (Clock<sup>Δ19</sup> or Csnk1e<sup>tau</sup> 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

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Knee Joint
Circadian Rhythm
Osteoarthritis
Tissue Inhibitor of Metalloproteinase-3
Catenins
Cartilage
Proteoglycans
Matrix Metalloproteinases
Phase shift
Homeostasis
Chemical activation
Photoperiod
Enzymes
Joints
Articular Cartilage
Locomotion
Chondrocytes
Down-Regulation

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

Kc, R., Li, X., Voigt, R. M., Ellman, M. B., Summa, K. C., Vitaterna, M. H., ... 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

Environmental Disruption of Circadian Rhythm Predisposes Mice to Osteoarthritis-Like Changes in Knee Joint. / Kc, Ranjan; Li, Xin; Voigt, Robin M.; Ellman, Michael B.; Summa, Keith C.; Vitaterna, Martha Hotz; Keshavarizian, Ali; Turek, Fred W.; Meng, Qing Jun; Stein, Gary S.; van Wijnen, Andre J; Chen, Di; Forsyth, Christopher B.; Im, Hee Jeong.

In: Journal of Cellular Physiology, Vol. 230, No. 9, 01.09.2015, p. 2174-2183.

Research output: Contribution to journalArticle

Kc, R, Li, X, Voigt, RM, Ellman, MB, Summa, KC, Vitaterna, MH, Keshavarizian, A, Turek, FW, Meng, QJ, Stein, GS, van Wijnen, AJ, Chen, D, Forsyth, CB & Im, HJ 2015, 'Environmental Disruption of Circadian Rhythm Predisposes Mice to Osteoarthritis-Like Changes in Knee Joint', Journal of Cellular Physiology, vol. 230, no. 9, pp. 2174-2183. https://doi.org/10.1002/jcp.24946
Kc, Ranjan ; Li, Xin ; Voigt, Robin M. ; Ellman, Michael B. ; Summa, Keith C. ; Vitaterna, Martha Hotz ; Keshavarizian, Ali ; Turek, Fred W. ; Meng, Qing Jun ; Stein, Gary S. ; van Wijnen, Andre J ; Chen, Di ; Forsyth, Christopher B. ; Im, Hee Jeong. / Environmental Disruption of Circadian Rhythm Predisposes Mice to Osteoarthritis-Like Changes in Knee Joint. In: Journal of Cellular Physiology. 2015 ; Vol. 230, No. 9. pp. 2174-2183.
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